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1
Filho, José Dantas Ribeiro, Paulo Vinícius de Morais Santos, Samuel Rodrigues Alves, Lorena Chaves Monteiro, Caio Monteiro Costa, Rinaldo Batista Viana, Marcel Ferreira Bastos Avanza, Waleska de Melo Ferreira Dantas, and Micheline Ozana da Silva. "Effects of time and temperature on blood gas and electrolytes in equine venous blood." Acta Veterinaria Brno 89, no. 3 (2020): 239–46. http://dx.doi.org/10.2754/avb202089030239.
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This study aimed to evaluate the viability time of horse venous blood samples kept at laboratory temperature (LT) and in water with ice (WI), to perform blood gas analysis. Eleven blood samples were collected in duplicates from 10 healthy horses. The samples were transported to the laboratory and subjected to one of the 24 h storage method. Each pair of syringes was distinctly kept at LT or submerged in WI. Blood gas tests were performed at times T0h, T1h, T2h, T3h, T4h, T5h, T6h, T8h, T10h, T12h and T24h after collection. Analyses of electrolytes were also performed from the same samples. A difference in blood pH was found between the treatments (P < 0.05). From T4h, pH decreased in samples kept at LT, but in WI, pH did not change. For partial pressure of carbon dioxide (pCO2), a difference between treatments (P < 0.05) was noted starting at T8h. In samples kept at LT, pCO2 increased; no changes occurred in samples stored in WI. There was a decrease in the base concentration beginning at T5h in samples kept at LT (P < 0.05), but no variation in samples kept in WI. These changes can be attributed to the erythrocyte metabolism, still active in vitro, which generates lactic acid from anaerobic glycolysis. The potassium concentration increased in samples kept in WI from T4h, with a gradual increase until T24h. Conservation of equine venous blood samples in WI is efficient in reducing cellular metabolism, thereby increasing the viability of samples for examination and interpretation of results.
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Vaca, Alicia, Mariela Sivina, Karen Clise-Dwyer, Ekaterina Kim, Michael J. Keating, Alessandra Ferrajoli, William G. Wierda, Dan Li, Qing Ma, and Jan A. Burger. "Expansion of T Helper Cell Subsets in Chronic Lymphocytic Leukemia Cell Co-Cultures with Nurselike Cells." Blood 134, Supplement_1 (November 13, 2019): 1746. http://dx.doi.org/10.1182/blood-2019-125827.
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Background: In secondary lymphatic organs (SLO), chronic lymphocytic leukemia (CLL) cells form characteristic pseudo-follicles, also called proliferation centers, in which proliferating CLL cells are in intimate contact with CD4+ T helper cells. Despite evidence for a co-evolution of CLL cells and counterpart T helper cells, the prevalence and dynamics of T cell subsets, such as T follicular helper cells (TFH), T regulatory helper cells (TRegs) and IL-17-producing T helper cells (Th17) has not been characterized in detail. The CLL nurselike cell (NLC) model recapitulates key cellular and molecular interactions between CLL cells and the microenvironment in SLO, based on functional and gene expression studies, and represents a valid in vitro model for the SLO microenvironment in CLL. To gain insight into the potential role of T cells in CLL SLO, we utilized the NLC model to characterize T helper cell subsets and their dynamics in NLC co-cultures. Methods and Results: First, we quantified CD4+ and CD8+ T cell subsets in fresh peripheral blood mononuclear cell (PBMC) samples from 14 patients and then placed 1x107 PBMCs/ml in culture to establish NLC. We rechecked the relative proportion of CD4+ and CD8+ T cells, as well as absolute T cell counts, and their viability after 3, 6, 9, 12 and 14 days in NLC co-culture conditions. Interestingly, throughout the 14 days of culture, the number of T helper cells remained stable when compared to baseline samples. Next, we characterized T helper cell subsets in 25 different CLL samples, comparing CD4+ T cell subsets in freshly isolated CLL PBMC with matched samples harvested after 14 days of NLC culture. Samples were stained with subset-specific fluorescence-labeled antibody combinations, and analyzed by flow cytometry. NLC co-culture resulted in a significant expansion of TFH and TReg cells. TFH absolute cell counts assessed by flow cytometry using counting beads, increased from 9.4±2.2/μl at baseline to 29.0±5.9/μl in NLC co-cultures (n=14, p=0.001) and TReg from 17.0±3.3/μl to 51.0±15.0/μl (n=14, p=0.027). In contrast, Th17 absolute cell counts declined after 14 days of culture from 113.0±21.0/μl to 68.0±13.0/μl (n=14, p=0.001). Moreover, TH2 cells declined from 42.0±7.4/μl to 30.0±8.2/μl (n=14, p=0.005). Next, we analyzed for changes in TFH subsets (TFH1, TFH2 and TFH17). When compared to TFH cells from CLL PBMC, NLC culture resulted in a relative increase in TFH2 from 17.0±2.4% to 26.0±1.7% (n=25, p=0.013), and in TFH17 from 12.0±1.6% to 21.0±2.7% (n=25, p=0.006) In contrast, TFH1 frequency decreased after 14 days of culture (54.0±3.5% versus 34.0±2.9%, n=25, p=0.001). T follicular regulatory (TFr) cells also increase under co-culture conditions from undetectable to 4.8±1.9% (n=25, p=0.025)(Figure1). Looking at the maturity of CD4+ cells we noted a relative increase of central memory cells from 42.0±3.2% to 50.0±3.2% (n=25, p=0.023), whereas effector memory cells decreased from 34.0±3.4% to 26.0±2.7% (n=25, p=0.009), the fraction of naïve CD4+ cells remained unchanged. Next, we assessed the activation status of co-inhibitory receptors on CD3+CD4+ cells. We found a significant relative increase in CD4+ T cells expressing PD1 and CTLA-4 after 14 days of culture. Additionally, the TFH and TReg subsets demonstrated a significantly higher CTLA-4 expression after culture while TReg cells also addressed an increase in PD1 frequency. Furthermore, we observed a significantly higher CD28 expression on TFH and TReg subsets after 14 days of co-culture. Following, to address the residence and migration capacity of T cells in NLC co-cultures, we analyzed the CD69 and CD62L expression. Our results revealed significantly higher expression of CD69 in NLC co-cultures, whereas CD62L levels remained unchanged. Conclusion: The expansion of TFH and TReg cells in NLC co-cultures suggests the selection and clonal expansion of T cells that may support and engage in crosstalk with CLL cells. Additionally, the expansion of TFr and TFH17 cells could reflect a milieu of immune tolerance establishing in NLC co-cultures. Ongoing TCR sequencing of serial CD4+ T cell samples (baseline versus 14 days under NLC conditions) will characterize changes of clonal architecture in the T helper cell compartment, and will further improve our understanding of co-evolution of CLL and T helper cells. Disclosures Wierda: Gilead Sciences: Research Funding; Juno Therapeutics: Research Funding; KITE pharma: Research Funding; Sunesis: Research Funding; Miragen: Research Funding; Janssen: Research Funding; Xencor: Research Funding; Acerta Pharma Inc: Research Funding; Pharmacyclics LLC: Research Funding; Genentech: Research Funding; AbbVie: Research Funding; GSK/Novartis: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Cyclcel: Research Funding; Loxo Oncology Inc.: Research Funding. Burger:Aptose Biosciences, Inc: Research Funding; BeiGene: Research Funding; Gilead Sciences: Research Funding; AstraZeneca: Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Pharmacyclics, an AbbVie company: Research Funding.
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DiToro, Daniel F., Colleen J. Winstead, Rakieb Andargachew, Carlene Zindl, Carson Edward Moseley, Duy Pham, Brian D. Evavold, and Casey Todd Weaver. "IL2 production predicts Tfh differentiation." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 150.18. http://dx.doi.org/10.4049/jimmunol.198.supp.150.18.
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Abstract Naïve CD4 T cells differentiate into functionally distinct subsets in response to a set of extrinsic and intrinsic cues. Effector subsets, including Th1, Th2 and Th17 CD4s, are required for optimal cellular responses to invading pathogens, while class switched antibody responses depend on the differentiation of T follicular helper cells (Tfh). Development of both Tfh and non-Tfh occurs in parallel and involves two distinct but functionally related expression bifurcations. Upon formation of T cell receptor (TCR)/major histocompatibility (MHC) synapses with antigen-presenting cells (APC), a discrete subset of activated T cells secretes the cytokine IL2. Similarly, a portion of activated cells express the transcription factor Bcl6 and differentiate into Tfh cells, while the remainder express Blimp1 and develop into effector CD4s. However, the cellular, temporal and mechanistic relationships between these two bifurcations remain unclear. Here we show that the IL2 and Bcl6/Blimp1 expression bifurcations occur simultaneously, precede cell division, predict differentiation into Tfh and non-Tfh subsets, and are mechanistically related to antigen availability TCR density.
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Choi, Seung-Chul, Anton Titov, Georges Abboud, and Laurence Morel. "Autoreactive and immunization-induced follicular helper T cells have opposite glucose and glutamine requirements." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 163.7. http://dx.doi.org/10.4049/jimmunol.200.supp.163.7.
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Abstract Both glycolysis and mitochondrial oxidative metabolism are elevated in CD4+ T cells from lupus-prone mice, and metabolic inhibitors targeting both of these pathways normalized lupus T cell functions in vitro and reverted disease in mice. Here, we showed that inhibiting glucose metabolism with 2-deoxy-D-glucose (2DG) results in a drastic reduction of follicular helper T (TFH) cell frequency in lupus-prone B6.Sle1.Sle2.Sle3 (TC) mice. However, treatment of TC mice with 2DG had little effect on the production of antibodies or the expansion of TFH cells following immunization with a nominal antigen of T-cell-dependent (TD) humoral responses, and no effect on the frequency of influenza virus-specific TFH cells induced by immunization with PR8 influenza virus. Thus, TFH cells supporting the production of autoantibodies are different from TFH cells providing protective humoral immunity against pathogens. The specific metabolic signature from autoimmune TFH cell is significantly different compared with exogenous antigen-specific TFH cells. Further results obtained with gene expression analysis and treatment with metabolic inhibitors indicated that autoreactive TFH cells depend on glucose metabolism, while exogenous antigen-specific TFH cells are more glutamine-demanding. Overall, our results predict that targeting TFH cellular metabolism provides an effective and safe therapeutic approach for systemic autoimmunity by eliminating autoreactive TFH cells.
5
Padhan, Kartika, Eirini Moysi, Alessandra Noto, Alexander Chassiakos, Khader Ghneim, Maria Maddalena Perra, Sanjana Shah, et al. "Acquisition of optimal TFH cell function is defined by specific molecular, positional, and TCR dynamic signatures." Proceedings of the National Academy of Sciences 118, no. 18 (April 26, 2021): e2016855118. http://dx.doi.org/10.1073/pnas.2016855118.
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The development of follicular helper CD4 T (TFH) cells is a dynamic process resulting in a heterogenous pool of TFH subsets. However, the cellular and molecular determinants of this heterogeneity and the possible mechanistic links between them is not clear. We found that human TFH differentiation is associated with significant changes in phenotypic, chemokine, functional, metabolic and transcriptional profile. Furthermore, this differentiation was associated with distinct positioning to follicular proliferating B cells. Single-cell T cell receptor (TCR) clonotype analysis indicated the transitioning toward PD-1hiCD57hi phenotype. Furthermore, the differentiation of TFH cells was associated with significant reduction in TCR level and drastic changes in immunological synapse formation. TFH synapse lacks a tight cSMAC (central supra molecular activation Cluster) but displays the TCR in peripheral microclusters, which are potentially advantageous in the ability of germinal center (GC) B cells to receive necessary help. Our data reveal significant aspects of human TFH heterogeneity and suggest that the PD-1hiCD57hi TFH cells, in particular, are endowed with distinctive programming and spatial positioning for optimal GC B cell help.
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Zander, Ryan A., Gang Xin, David Schauder, and Weiguo Cui. "T follicular helper cell-derived IL-10 sustains humoral immunity during chronic viral infection." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 122.2. http://dx.doi.org/10.4049/jimmunol.198.supp.122.2.
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Abstract Although it is well-appreciated that Tfh cells play a critical role in regulating antiviral humoral immunity, the detailed cellular and molecular pathways that govern their differentiation and function during chronic viral infection remains incompletely understood. In this study, we generated IL-10 and IL-21 double-reporter mice to study the dynamic expression of the immunoregulatory cytokines IL-10 and IL-21, which are known to differentially regulate T cell-mediated control over viral replication. Infection of these double-reporter mice with either an acute or chronic strain of LCMV, revealed a unique subset of IL-10+IL-21+co-producing Tfh cells that arise only during chronic viral infection. Notably, compared to IL-21-single producing Tfh cells, IL-10+IL-21+co-producing Tfh cells exhibited an enhanced germinal center (GC) Tfh-like profile, as exemplified by their increased per cell expression of PD-1, CXCR5, and Bcl-6. Additional analyses identified that IL-10-producing Tfh cells have an increased capacity to form stable Tfh-B cell conjugates compared to their IL-10− Tfh counterparts, suggesting that IL-10+ Tfh cells may specialize in providing help signals to B cells during chronic infection. Importantly, depletion of IL-10+IL-21+ co-producing CD4 T cells or deletion of Il10 specifically from Tfh cells resulted in impaired GC B cell responses, LCMV-specific antibody production and viral control. Mechanistically, we show that B cell intrinsic IL-10 signaling is indispensable for GC B cell differentiation and function. Collectively, our findings delineate a heterogeneous population of Tfh cells and elucidate a critical role for Tfh-derived IL-10 in promoting humoral immunity during persistent viral infection.
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Houser, Cassandra L. "Aryl hydrocarbon receptor regulation of T follicular helper cells during respiratory viral infection." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 24.02. http://dx.doi.org/10.4049/jimmunol.206.supp.24.02.
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Abstract The aryl hydrocarbon receptor (AHR) is a ligand-regulated transcription factor that binds structurally diverse molecules from the environment, including pollutants, dietary factors, and chemicals from microorganisms. AHR-binding compounds alter adaptive immune responses, but the cellular components affected and governing mechanisms are not fully defined. For instance, AHR activation affects antibody responses; a process for which T follicular helper cells (Tfh cells) are critical. We recently discovered that AHR activation alters the percentage and number of Tfh cells during influenza A virus (IAV) infection. Yet, how the AHR modulates Tfh cells is not known. The present work shows that AHR-mediated changes to Tfh cells are due to changes in CD4+ T cell proliferation and BCL6 expression, an essential transcription factor for Tfh cell differentiation. Utilizing conditional AHR knockout mice, we show that changes to Tfh cells require AHR expression in CD4+ T cells. The AHR regulates gene expression directly, via its DNA-binding domain (DBD), and indirectly via other signaling molecules. To delineate which pathways it uses to modulate Tfh cells, we used mice with a mutated AHR DBD and demonstrate that it requires its cognate DBD to regulate Tfh cells during infection. This supports that AHR modulates Tfh cells by directly regulating gene expression. Overall, these findings provide new information about how AHR signaling influences humoral immunity to a common respiratory pathogen. Given that exposure to AHR-binding pollutants impacts immune responses to infections and vaccines, better understanding of the mechanisms that control Tfh cell responses has broad reaching impact on immune defenses and immune-mediated diseases.
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Petrovas, Constantinos, Takuya Yamamoto, Michael Gerner, Kristin Boswell, Mario Roederer, Robert Seder, Ronald Germain, Elias Haddas, and Richard Koup. "Increased immune activation during chronic SIV infection drives the TFH dynamics. (105.33)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 105.33. http://dx.doi.org/10.4049/jimmunol.188.supp.105.33.
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Abstract We have investigated the phenotype, location, molecular signature and function of follicular CD4 T helper cells (TFH) in rhesus macaques. Similar to human TFH, they are characterized by a CCR7lowPD-1highICOShighCTLA-4highCXCR4high phenotype and represent a heterogeneous population with respect to cytokine function. PD-1high CD4 cells were localized closer to the follicle center than PD-1low CD4 cells. This relative cellular distribution was not affected by the SIV infection. Production of Th1 cytokines was compromised while IL-4 was secreted predominantly by a highly differentiated (CD150low) subpopulation of TFH cells. Compared to non-TFH cells, TFH cells exhibited a distinct gene profile that was significantly altered by SIV infection. A significant reduction in the expression of the IL-4 gene in TFH was found implying a defective help for the development of B cell responses during chronic SIV. CD150low TFH cells were characterized by defective survival while in vivo BrdU integration studies revealed a defective cycling capacity of these cells. Preferential infection of TFH cells was found only during acute SIV yet progression to chronic SIV resulted in their accumulation, which was associated with high immune activation and altered IL-6-induced signaling. Thus, the preservation of TFH in the face of high rates of infection can be explained by their normally short half-life and the diverse populations of CD4 T cells that can provide to their continual replenishment.
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Kang, Seung Goo, Wen-Hsien Liu, John Teijaro, Hyung Wook Lim, Jovan Shepherd, Eric Verdin, Hai Qi, Michael Oldstone, and Changchun Xiao. "MiR-17~92 family microRNAs are critical regulators of T follicular helper cell differentiation (P1133)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 50.9. http://dx.doi.org/10.4049/jimmunol.190.supp.50.9.
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Abstract Germinal center (GC) reaction is a key event in B cell-mediated immune responses and CD4+ T cell help plays an essential role in these process. A distinct CD4+ effector T cell subset, T follicular helper cells (TFH), provides this help to B cells. However, molecular mechanisms underlying TFH differentiation are still largely unknown. A recent study revealed that Bcl-6 is a signature transcription factor regulating TFH differentiation and it represses the expression of miR-17~92 in CD4+ T cells. MiR-17~92 in turn suppresses the expression of CXCR5, a critical chemokine receptor controlling CD4+ T cell migration into B cell follicles. The authors therefore concluded that miR-17~92 functions as a negative regulator of TFH differentiation. Here we report the surprising finding that mice with miR-17~92 family microRNAs (miRNAs) deleted specifically in T cells exhibited severely compromised TFH differentiation, germinal center formation, and reduced antibody responses upon protein antigen immunization. Those mutant mice were also defective in TFH differentiation and germinal center B (GCB) cell formation during lymphocytic choriomeningitis virus (LCMV) clone-13 infection and failed to control the virus. Conversely, T cell-specific miR-17~92 transgenic mice spontaneously accumulated TFH cells. Novel cellular and molecular mechanisms underlying miR-17~92 family miRNA-mediated regulation of TFH differentiation will be presented at this meeting.
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Liu, Wen-Hsien, Seung Goo Kang, Zhe Huang, Cheng-Jang Wu, Hyun Yong Jin, Christian J. Maine, Yi Liu, et al. "A miR-155–Peli1–c-Rel pathway controls the generation and function of T follicular helper cells." Journal of Experimental Medicine 213, no. 9 (August 1, 2016): 1901–19. http://dx.doi.org/10.1084/jem.20160204.
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MicroRNA (miRNA) deficiency impairs the generation of T follicular helper (Tfh) cells, but the contribution of individual miRNAs to this phenotype remains poorly understood. In this study, we performed deep sequencing analysis of miRNAs expressed in Tfh cells and identified a five-miRNA signature. Analyses of mutant mice deficient of these miRNAs revealed that miR-22 and miR-183/96/182 are dispensable, but miR-155 is essential for the generation and function of Tfh cells. miR-155 deficiency led to decreased proliferation specifically at the late stage of Tfh cell differentiation and reduced CD40 ligand (CD40L) expression on antigen-specific CD4+ T cells. Mechanistically, miR-155 repressed the expression of Peli1, a ubiquitin ligase that promotes the degradation of the NF-κB family transcription factor c-Rel, which controls cellular proliferation and CD40L expression. Therefore, our study identifies a novel miR-155–Peli1–c-Rel pathway that specifically regulates Tfh cell generation and function.
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Lin, Xuan, Longyun Ye, Xu Wang, Zhenyu Liao, Jia Dong, Ying Yang, Rulin Zhang, et al. "Follicular Helper T Cells Remodel the Immune Microenvironment of Pancreatic Cancer via Secreting CXCL13 and IL-21." Cancers 13, no. 15 (July 22, 2021): 3678. http://dx.doi.org/10.3390/cancers13153678.
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Immunosuppression is an important factor for the poor prognosis of pancreatic ductal adenocarcinoma (PDAC). Follicular helper T cells (Tfh cells) play an anti-tumor role in various malignant solid tumors and predict better patient prognosis. In the present study, we aimed to determine the immunosuppressive mechanism associated with Tfh cells and explore a new strategy to improve the tumor microenvironment of PDAC. Flow cytometry was used to detect the infiltration and proportion of Tfh cells in tumor tissues and peripheral blood from patients with PDAC. The spatial correlations of Tfh cells with related immune cells were evaluated using immunofluorescence. The function of Tfh cells was examined using in vitro and in vivo model systems. The high infiltration of Tfh cells predicted better prognosis in patients with PDAC. Tfh cells recruited CD8+ T cells and B cells by secreting C-X-C motif chemokine ligand 13 (CXCL13), and promoted the maturation of B cells into antibody-producing plasma cells by secreting interleukin 21 (IL-21), thereby promoting the formation of an immunoactive tumor microenvironment. The function of Tfh cells was inhibited by the programmed cell death 1 ligand 1 (PD-L1)/programmed cell death 1 (PD-1) signaling pathway in PDAC, which could be reversed using neoadjuvant chemotherapy. Treatment with recombinant CXCL13, IL-21 and Tfh cells alleviated tumor growth and enhanced the infiltration of CD8+ T cells and B cells, as well as B cell maturation in a PDAC mouse model. Our results revealed the important role of Tfh cells in mediating anti-tumor cellular immunity and humoral immunity in PDAC via secreting CXCL13 and IL-21 and determined a novel mechanism of immunosuppression in PDAC.
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Zhang, Xin, Shikha Singla, Jerry Pound, Jerald Zakem, Kismet Collin, Tamika Webb-Detiege, William Davis, and Robert Quinet. "Identification of follicular helper T cells as a novel cell population potentially involved in the pathogenesis of Rheumatoid Arthritis (HUM3P.251)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 121.11. http://dx.doi.org/10.4049/jimmunol.194.supp.121.11.
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Abstract Background. RA is an autoimmune disease characterized by chronic inflammation of the synovium, causing progressive joint destruction. The treatment for RA is largely based on the clinic manifestations, which are remote from the fundamental pathophysiologic defects. Identification of cellular subsets or biomarkers is a necessary first step toward more accurate prognosis and better therapeutic decisions. Here, we identified a novel T cell subset, follicular helper T cells (Tfh) in RA patients, and examined the hypothesis that Tfh cells may account for RA pathogenesis by providing a fostering environment for self-reactive B cells, resulting in autoantibody production. Methods. Peripheral blood was collected from 26 RA patients and healthy donors. Synovial fluid from actively inflamed joints of RA patients was also collected. Clinical disease activity (DAS-28) and serum laboratory results were obtained. Tfh cells were defined by their signature surface markers via flow cytometry. IL-21 expression and plasmablasts were measured by intracellular staining. Results. A novel T cell subset with Tfh cell signature molecule and cytokine was expanded in the peripheral blood of active RA patients. The percentage of Tfh cells correlated positively with the level of pathogenic auto-antibody (anti-CCP) and disease activity. Conclusions. Circulating Tfh cells may serve as a biomarker of pathogenesis in RA patients. Targeting RA-Tfh cells may provide earlier and precise treatment strategies.
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Choi, Seung-Chul, Yiming Yin, and Laurence Morel. "Metabolic inhibitors elimiante the expansion of autoimmune follicular helper T cells but not that induced by T-dependent-immunization in lupus mice." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 118.8. http://dx.doi.org/10.4049/jimmunol.196.supp.118.8.
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Abstract The expansion of follicular helper CD4 T (Tfh) cells is tightly associated with disease severity in lupus patients, following multiple studies in various mouse models showing that they are necessary for the production of class-switched high-affinity pathogenic autoAbs. We have recently shown that both glycolysis and mitochondrial oxidative metabolism are elevated in CD4 T cells from lupus prone B6.Sle1.Sle2.Sle3 (TC) mice as compared to B6 controls, and that a treatment combining 2-deoxy-D-glucose (2-DG), which inhibits glucose metabolism, and metformin, which inhibits oxygen consumption, normalized lupus T cell functions in vitro and reverted disease. We have expanded these results to B6.lpr, BXSB.Yaa and NZB/WF1 models of lupus. Remarkably, the number and the frequency of Tfh cells was normalized in these 4 models of lupus treated with a combination of 2DG and metformin, corresponding to a drastic reduction of autoantibodies. Treatment of normal or lupus-prone mice with the same inhibitors had however little effect on the production of TD antibodies or the expansion of Tfh cells following immunization with a nominal antigen. This suggests that Tfh cells supporting the production of autoAbs are quantitatively or qualitatively different from Tfh cells providing protective humoral immunity against pathogens. Moreover, it suggests that autoimmune Tfh cells have higher metabolic requirements than the metabolically quiescent Tfh cells that have been recently described in TD-responses. Studies to characterize the specific metabolic requirements of autoimmune Tfh cells are ongoing. Overall, our results predict that targeting Tfh cellular metabolism provides an effective and safe therapeutic approach for systemic autoimmunity.
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Louis, Kevin, Camila Macedo, Elodie Bailly, Louis Lau, Bala Ramaswami, Marilyn Marrari, Douglas Landsittel, et al. "Coordinated Circulating T Follicular Helper and Activated B Cell Responses Underlie the Onset of Antibody-Mediated Rejection in Kidney Transplantation." Journal of the American Society of Nephrology 31, no. 10 (July 28, 2020): 2457–74. http://dx.doi.org/10.1681/asn.2020030320.
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BackgroundAlthough antibody-mediated rejection (ABMR) has been long recognized as a leading cause of allograft failure after kidney transplantation, the cellular and molecular processes underlying the induction of deleterious donor-specific antibody (DSA) responses remain poorly understood.MethodsUsing high-dimensional flow cytometry, in vitro assays, and RNA sequencing, we concomitantly investigated the role of T follicular helper (TFH) cells and B cells during ABMR in 105 kidney transplant recipients.ResultsThere were 54 patients without DSAs; of those with DSAs, ABMR emerged in 20 patients, but not in 31 patients. We identified proliferating populations of circulating TFH cells and activated B cells emerging in blood of patients undergoing ABMR. Although these circulating TFH cells comprised heterogeneous phenotypes, they were dominated by activated (ICOS+PD-1+) and early memory precursor (CCR7+CD127+) subsets, and were enriched for the transcription factors IRF4 and c-Maf. These circulating TFH cells produced large amounts of IL-21 upon stimulation with donor antigen and induced B cells to differentiate into antibody-secreting cells that produced DSAs. Combined analysis of the matched circulating TFH cell and activated B cell RNA-sequencing profiles identified highly coordinated transcriptional programs in circulating TFH cells and B cells among patients with ABMR, which markedly differed from those of patients who did not develop DSAs or ABMR. The timing of expansion of the distinctive circulating TFH cells and activated B cells paralleled emergence of DSAs in blood, and their magnitude was predictive of IgG3 DSA generation, more severe allograft injury, and higher rate of allograft loss.ConclusionsPatients undergoing ABMR may benefit from monitoring and therapeutic targeting of TFH cell–B cell interactions.
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Zeng, Hu, Xian Zhou, Yanfeng Li, and Anne Davidson. "mTORC2 contributes to murine lupus associated immunopathology." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 103.02. http://dx.doi.org/10.4049/jimmunol.208.supp.103.02.
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Abstract The development of systemic lupus erythematosus (SLE) is associated with overactivation of the type I interferon (IFN) pathway, lymphopenia, and increased follicular helper T (Tfh) cell differentiation. However, the cellular and molecular mechanisms of action of type I IFN in SLE remains incompletely understood. Here we show that type I IFN activates the mechanistic target of rapamycin complex 2 (mTORC2) in T cells to promote T cell lymphopenia. mTORC2 also promotes Tfh differentiation and disrupts Treg homeostasis. Inactivation of mTORC2 greatly ameliorated the immunopathology in a lupus-prone mouse model, associated with reduced Tfh differentiation, normalization of Treg homeostasis and reduced T cell glucose metabolism. These data indicate that mTORC2 acts downstream of type I IFN and costimulatory receptor ICOS, to promote T cell lymphopenia and Tfh differentiation in murine lupus development, suggesting that inhibition of mTORC2 could limit lupus disease progression. Supported by Lupus Research Alliance Mayo Foundation for Medical Education and Research R01AR077518
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Bonami, Rachel, Lindsay Nyhoff, Chrys Hulbert, Jamie Felton, Peggy L. Kendall, and James W. Thomas. "One size doesn’t fit all: SLAM-Associated Protein is dispensable for type 1 diabetes but required for autoantibody-mediated arthritis." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 115.14. http://dx.doi.org/10.4049/jimmunol.202.supp.115.14.
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Abstract Signaling lymphocytic activation molecule-associated protein (SAP), a critical intracellular signaling molecule for T-B interactions, drives Tfh development in germinal centers (GC) in the setting of protective immune responses. SAP promotes long-lived T cell-B cell interactions necessary to sustain germinal center reactions that lead to antibody production. High-affinity islet autoantibodies predict type 1 diabetes (T1D) but do not cause beta cell destruction. This paradox intimates T follicular helper cells (Tfh) as key pathologic effectors. To understand Tfh contribution to autoimmune processes, we investigated the role of SAP in T1D and autoantibody-mediated arthritis. Whereas spontaneous autoimmune arthritis depended on SAP, organized insulitis and diabetes onset were unabated, despite a blocked anti-insulin vaccine response. SAP-deficient T cell function was therefore investigated in the non-obese diabetic (NOD) T1D model. B lymphocyte antigen presentation drove SAP-deficient NOD T cell proliferation. Although germinal center B cell formation was markedly reduced, GC-Tfh were found at sites of autoimmune attack in SAP-deficient NOD mice. Thus, Tfh induced in germinal center reactions are dispensable for T1D and suggest that the autoimmune process in NOD retains pathogenic Tfh in the absence of prolonged B cell interactions. These findings demonstrate that SAP is essential for Tfh formation and autoimmunity when autoantibodies play a central role in autoimmune arthritis but not in cell-mediated T1D. SAP inhibition is thus a compelling strategy for autoantibody-mediated disease treatment, but additional cognate cellular interaction molecules must be targeted to treat cell-mediated autoimmune diseases.
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Sala, Eleonora, Marta Mangione, Chiara Laura, Eleonora Consolo, Cristian Gabriel Beccaria, Matteo Iannacone, and Mirela Kuka. "IFN-γ promotes TH1 at the expense of TFH differentiation during viral infections." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 182.24. http://dx.doi.org/10.4049/jimmunol.208.supp.182.24.
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Abstract Although humoral and cellular immunity upon viral infections usually co-exist, sometimes one of the two responses emerges and is responsible for most of the antiviral activity. For example, vescicular stomatitis virus (VSV) infection induces early and potent neutralizing antibody (nAb) responses, whereas lymphocytic choriomeningitis virus (LCMV) infection induces strong cellular responses, but weak nAb responses. Recent work from our laboratory has shown that unbalance is observed also at the level of CD4 T cells responses, with VSV inducing strong TFH polarization that support nAb responses, and LCMV in contrast promoting TH1 differentiation. Analysis of the VSV and LCMV priming niches led to identification of the spatiotemporal regulation of type I IFN expression as a critical regulator of antiviral CD4+ T cell polarization, with early type I IFN sensing leading to TFH polarization. Notably, this mechanism did not explain the strong TH1 differentiation observed during LCMV infection. In this study we aimed to elucidate the role of known TH1-polarizing cytokines in CD4+ T cell differentiation upon LCMV infection. We found that IFN-γ, but not IL-12, plays a key role in early CD4+ T cell differentiation upon LCMV infection, inducing TH1 cell polarization and suppressing TFH cell development, thus resulting in a shift in the equilibrium towards TFH and humoral responses. Future studies will determine the cellular source for this TH1-polarizing cytokine and the mechanism by which IFN-γ exerts its function, possibly unveiling the mechanisms underlying the reduced humoral response in the context of viral infections like LCMV.
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Shan, Zhiguo, Muhammad Farrukh Nisar, Mingxi Li, Chunhua Zhang, and Chunpeng (Craig) Wan. "Theaflavin Chemistry and Its Health Benefits." Oxidative Medicine and Cellular Longevity 2021 (November 18, 2021): 1–16. http://dx.doi.org/10.1155/2021/6256618.
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Huge epidemiological and clinical studies have confirmed that black tea is a rich source of health-promoting ingredients, such as catechins and theaflavins (TFs). Furthermore, TF derivatives mainly include theaflavin (TF1), theaflavin-3-gallate (TF2A), theaflavin-3 ′ -gallate (TF2B), and theaflavin-3,3 ′ -digallate (TF3). All of these TFs exhibit extensive usages in pharmaceutics, foods, and traditional medication systems. Various indepth studies reported that how TFs modulates health effects in cellular and molecular mechanisms. The available literature regarding the pharmacological activities of TFs has revealed that TF3 has remarkable anti-inflammatory, antioxidant, anticancer, antiobesity, antiosteoporotic, and antimicrobial properties, thus posing significant effects on human health. The current manuscript summarizes both the chemistry and various pharmacological effects of TFs on human health, lifestyle or aging associated diseases, and populations of gut microbiota. Furthermore, the biological potential of TFs has also been focused to provide a deeper understanding of its mechanism of action.
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Jha, Vibha, Lindsay K. Nicholson, Edward M. Gardner, Jeremy T. Rahkola, Harsh Pratap, and Edward N. Janoff. "Impact of HIV-1 infection and antigen class on T follicular helper (TFH) cell responses to pneumococcal polysaccharide-protein conjugate vaccine (PCV-13)." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 72.12. http://dx.doi.org/10.4049/jimmunol.202.supp.72.12.
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Abstract Pneumococcal infections are common and serious complications of HIV-1 disease. Prevention has been compromised by the limited magnitude and quality of antibody responses to T cell-independent (TI-2) pneumococcal capsular polysaccharides (PPS). The PCV-13 vaccine conjugates PPS to a T cell-dependent (TD) protein (diphtheria toxoid; DT). We investigated the differential response to PPS and DT by antibody-secreting B cells (ASC) after immunization with PCV-13 in newly-diagnosed healthy HIV+ and control adults. The numbers of PPS-specific IgG ASC increased significantly and similarly in HIV+ and controls 1 week after vaccination. However, DT-specific IgG ASC increased significantly in controls but not HIV+ subjects. To determine the cellular basis of these disparate responses to DT and PPS, we characterized the frequency and activation of T follicular helper (TFH) cells, the predominant T cell subset providing B cell help. The percentages of and intracellular IL-21 in TFH cells were unchanged with vaccination. However, expression of ICOS, which sustains TFH function and phenotype, increased significantly after vaccination among controls, but not the HIV+ group. Increases in ICOS+ TFH correlated with changes in TD DT-specific IgG ASC in controls but not in HIV+. In contrast, ICOS expression did not correlate with TI-2 PPS-specific ASC in either group. Levels of TFH differentiating factors IL-12 and IL-6 increased post vaccination only in controls. In summary, although TI-2 PPS-specific responses were similar in both groups and independent of TFH activation, TFH ICOS-expression was most closely related to responses to TD DT, which were compromised even in recently diagnosed healthy HIV+ adults.
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Lopez-Ocasio, Maria D., and Ethan M. Shevach. "T Follicular Regulatory (TFR) Cells Regulate B Cell Responses By Targeting TF Helper (TFH) Cells." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 223.11. http://dx.doi.org/10.4049/jimmunol.198.supp.223.11.
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Abstract Interaction of TFH cells with B cells not only helps TFH to fully commit to this lineage, but also provides B cells with survival and differentiation cues. A GC response is critical for the development of an immune response against pathogens, but a dysregulated response could lead to autoantibody production. TFR cells, a subset of Foxp3+ Tregs, localize into follicles to regulate GC responses. To elucidate the mechanism (s) and cellular target (s) utilized by TFR cells to suppress GC responses, we quantitated TFR function in vitro. In the absence of TFR cells, TFH from primed mice induce both naive B cell differentiation into GC B cells and class switching in the presence of anti-CD3 alone or anti-IgM/anti-CD3 in a contact dependent manner. Addition of TFR cells from primed mice efficiently suppressed GC B cell proliferation, differentiation and class switching in the anti-CD3 alone cultures, but only moderately suppressed BCR-stimulated B cells. Under anti-CD3 conditions, IL-4-deficient TFH cells did not promote B cell differentiation and class switching. In contrast, IL-21R-deficient B cells differentiated into GC B cells with a reduced number of IgG1+ cells. When IL-4 deficient TFH cells were co-cultured with IL-21R-deficient B cells, both GC differentiation and class switching were reduced. Under anti-IgM/anti-CD3 conditions, IL-4-deficient TFH cells promoted B cell differentiation, but class switching was reduced, while IL-21R-deficient B cells differentiated normally into GC B cells, but class switching was reduced. These studies suggest that at least in vitro, TFR cells regulate the GC responses by acting directly on TFH cells most likely by inhibiting cytokine production.
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Bowlin, Marvin Q., John E. Bradley, Allan J. Zajac, Daniel C. Bullard, and Troy D. Randall. "The LFA1 ligand, CD54, is not required for the differentiation of TFH cells or germinal center formation." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 152.9. http://dx.doi.org/10.4049/jimmunol.198.supp.152.9.
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Abstract In germinal centers (GC), B cells undergo cellular proliferation and affinity maturation, and ultimately differentiate into either high-affinity antibody-secreting cells (ASCs) or memory B cells. GC B cells present antigen to T follicular helper (TFH) cells in order to elicit survival and proliferation signals. The integrin, Lymphocyte Function-Associated Antigen 1 (LFA1), is required for this process, as mice lacking LFA1 or treated with LFA1 blocking antibodies fail to form GCs or TFH cells. We hypothesized that the counter-receptor for LFA1, ICAM-1 or CD54, would be similarly required for GC formation and TFH differentiation. To test this hypothesis, we infected CD54-deficient (KO) and wild-type (WT) mice with influenza virus (PR8) and enumerated ASCs and GC B cells on days 7, 9, and 14. We found that KO mice had more GC B cells than WT mice on days 9 and 14, but observed no difference in the number of ASCs or TFH cells. To determine if this result was intrinsic to the B cell lineage, we generated 50:50 (KO:WT) bone marrow chimeras. Following reconstitution, we infected the mice with PR8 and assayed donor-specific GC B cells and ASCs on days 9 and 14. On day 9, we found that GC B cells were highly enriched for KO cells, whereas the ASCs were highly enriched for WT cells. In contrast, TFH cells were represented equally in WT and KO populations. On day 14, we found that GC B cells were still highly enriched for KO cells, whereas there was no significant difference between WT and KO ASCs at this time. These results lead us to the surprising conclusion that, although the loss of LFA1 leads to the failure of TFH and GC responses, the loss of CD54 does not affect the TFH compartment and actually improves GC B cell responses.
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Gowthaman, Uthaman, Jennifer S. Chen, Biyan Zhang, William F. Flynn, Yisi Lu, Wenzhi Song, Julie Joseph, et al. "Identification of a T follicular helper cell subset that drives anaphylactic IgE." Science 365, no. 6456 (August 1, 2019): eaaw6433. http://dx.doi.org/10.1126/science.aaw6433.
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Cross-linking of high-affinity immunoglobulin E (IgE) results in the life-threatening allergic reaction anaphylaxis. Yet the cellular mechanisms that induce B cells to produce IgE in response to allergens remain poorly understood. T follicular helper (TFH) cells direct the affinity and isotype of antibodies produced by B cells. Although TFH cell–derived interleukin-4 (IL-4) is necessary for IgE production, it is not sufficient. We report a rare population of IL-13–producing TFH cells present in mice and humans with IgE to allergens, but not when allergen-specific IgE was absent or only low-affinity. These “TFH13” cells have an unusual cytokine profile (IL-13hiIL-4hiIL-5hiIL-21lo) and coexpress the transcription factors BCL6 and GATA3. TFH13 cells are required for production of high- but not low-affinity IgE and subsequent allergen-induced anaphylaxis. Blocking TFH13 cells may represent an alternative therapeutic target to ameliorate anaphylaxis.
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Lopez-Ocasio, Maria D. "T Follicular Regulatory (TFR) Cells Regulate B Cell Responses in Both, T-cell Dependent and Independent Pathways." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 48.9. http://dx.doi.org/10.4049/jimmunol.200.supp.48.9.
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Abstract Production of high-affinity antibody-secreting plasma cells and memory B cells requires interaction of TFH cells with B cells in the follicle. TFR cells, a subset of Foxp3+ Tregs, localize into follicles, regulating GC responses. To elucidate the mechanisms and cellular targets used by TFR cells to suppress GC responses, we quantitated their function in vitro. In the absence of TFR cells, TFH from primed mice induce naive B cell differentiation into GC B cells and class switching in the presence of anti-CD3 alone or anti-IgM/anti-CD3 in a contact dependent manner. Addition of TFR cells from primed mice efficiently suppressed GC B cell differentiation and class switching in the anti-CD3 alone cultures, but moderately suppressed BCR-stimulated B cells. Under anti-CD3 conditions, IL-4−/− TFH cells did not promote B cell differentiation and class switching. In contrast, IL-21R−/− B cells differentiated into GC B cells with a reduced number of IgG1+ cells. When IL-4−/− TFH cells were co-cultured with IL-21R−/− B cells, both GC differentiation and class switching were reduced. Under anti-IgM/anti-CD3 conditions, IL-4−/− TFH cells promoted B cell differentiation, but class switching was reduced, while IL-21R−/− B cells differentiated normally into GC B cells, with reduced class switching. When B cells alone were stimulated in culture with either LPS or CpG, TFR cells did not block B cell proliferation, but their differentiation into plasma cells was reduced. These studies suggest that in vitro, TFR cells regulate GC responses primarily by acting on TFH cells by inhibiting cytokine production and CD40L expression, but can also directly suppress some aspects of B cell differentiation. Supported by the Intramural Research Program of the NIAID.
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Ma, Cindy S., Elissa K. Deenick, Marcel Batten, and Stuart G. Tangye. "The origins, function, and regulation of T follicular helper cells." Journal of Experimental Medicine 209, no. 7 (July 2, 2012): 1241–53. http://dx.doi.org/10.1084/jem.20120994.
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The generation of high-affinity antibodies (Abs) plays a critical role in the neutralization and clearance of pathogens and subsequent host survival after natural infection with a variety of microorganisms. Most currently available vaccines rely on the induction of long-lived protective humoral immune responses by memory B cells and plasma cells, underscoring the importance of Abs in host protection. Ab responses against most antigens (Ags) require interactions between B cells and CD4+ T helper cells, and it is now well recognized that T follicular helper cells (Tfh) specialize in providing cognate help to B cells and are fundamentally required for the generation of T cell–dependent B cell responses. Perturbations in the development and/or function of Tfh cells can manifest as immunopathologies, such as immunodeficiency, autoimmunity, and malignancy. Unraveling the cellular and molecular requirements underlying Tfh cell formation and maintenance will help to identify molecules that could be targeted for the treatment of immunological diseases that are characterized by insufficient or excessive Ab responses.
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Reinhardt, Richard, Hong-Erh Liang, Brandon Sullivan, and Richard Locksley. "Divergent expression patterns of IL-4 and IL-13 define unique functions in type 2 immunity (56.22)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 56.22. http://dx.doi.org/10.4049/jimmunol.186.supp.56.22.
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Abstract Interleukin-4 (IL-4) and interleukin-13 (IL-13) are closely related cytokines critical to host responses against parasitic helminthes. We use reporter mice genetically engineered to mark cells producing IL-4 and IL-13 in vivo, allowing the temporal and spatial assessment of cytokine production at the single-cell level. In the lymph node, IL-4 is confined to T follicular helper (Tfh) cells. Unexpectedly, Tfh cells do not make IL-13. In contrast, tissue Th2 cells produce both cytokines. Divergent IL-4 and IL-13 production also occurs in innate immune cells. Basophils produce IL-4, while innate helper type-2 (Ih2) cells make only IL-13. Cytokine production by Th2 and Ih2 cells is intimately associated with high GATA-3 expression. Conversely, Tfh cells and basophils regulate IL-4 independently of GATA-3. Partitioning of the localization and cellular expression patterns of IL-4 and IL-13 helps explain the unique roles of these cytokines in anti-helminth and allergic immunity.
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Lai, Chen-Yen, Nimi Marcel, Allen W. Yaldiko, Arnaud Delpoux, and Stephen M. Hedrick. "A Bcl6 Intronic Element Regulates T Follicular Helper Cell Differentiation." Journal of Immunology 209, no. 6 (September 15, 2022): 1118–27. http://dx.doi.org/10.4049/jimmunol.2100777.
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Abstract In response to an intracellular infectious agent, the immune system produces a specific cellular response as well as a T cell–dependent Ab response. Precursor T cells differentiate into effector T cells, including Th1 cells, and T follicular helper (TFH) cells. The latter cooperate with B cells to form germinal centers and induce the formation of Ab-forming plasmacytes. One major focal point for control of T cell differentiation is the transcription factor BCL6. In this study, we demonstrated that the Bcl6 gene is regulated by FOXO1-binding, cis-acting sequences located in a highly conserved region of the first Bcl6 intron. In both mouse and human T cells, deletion of the tandem FOXO1 binding sites increased the expression of BCL6 and enhanced the proportion of TFH cells. These results reveal a fundamental control point for cellular versus humoral immunity.
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Anang, D., T. H. Ramwadhdoebe, J. Hahnlein, B. van Kuijk, S. Noortje, K. P. van Lienden, M. Maas, et al. "OP0099 INCREASED FREQUENCY OF CD4+ AND CD8+ FOLLICULAR HELPER T CELLS IN HUMAN LYMPH NODE BIOPSIES DURING THE EARLIEST STAGES OF RHEUMATOID ARTHRITIS." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 65.2–66. http://dx.doi.org/10.1136/annrheumdis-2022-eular.289.
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BackgroundFollicular T helper (Tfh) cells provide key help for B cell differentiation into plasma and memory B cells and are essential in germinal center formation and (auto) antibody generation (1).ObjectivesTo gain more insights into the role of Tfh cells in RA development, we assessed whether Tfh cells have an altered frequency, phenotype and cytokine profile in peripheral blood, lymphoid and synovial tissues during the earliest stages of RA development.MethodsUsing flow cytometry, we analyzed the phenotpe, frequencies and cytokine profile of Tfh cells and B cells in peripheral blood and lymph node biopsies of healthy controls (HCs), autoantibody positive individuals at risk for developing RA (RA-risk individuals), and early RA patients. Using immunofluorescene we confirmed the presence of Tfh in B cell follicles of lymph nodes and synovial tissue biopsies of RA patients.ResultsIn blood, the frequency of Tfh cells did not differ between study groups. In lymphoid and synovial tissue, Tfh cells were localized in B-cell areas, and their frequencies correlated strongly with the frequency of CD19+ B cells. Compared to lymphoid tissue of healthy controls, that of RA patients and RA-risk individuals, showed more CD19+ B cells and more CD4+CXCR5+ and CD8+CXCR5+ follicular T cells. Of note, compared to healthy controls, specifically lymph node Tfh cells of RA-risk and early RA patients produced less IL-21 upon ex-vivo stimulation.ConclusionTfh cells are localised in B-cell rich areas in lymphoid and synovial tissues of early RA patients. The analysis of lymph node tissue in early RA patients showed increased frequencies of Tfh cells, where they clearly associate with B cells. Interestingly, IL-21 production is already aberrant in the very early at risk phase of the disease. Our data suggest that Tfh cells may present a novel rationale for therapeutic targeting during the preclinical stage of RA to prevent further disease progression.References[1]Ise W, Fujii K, Shiroguchi K, Ito A, Kometani K, Takeda K, et al. T Follicular Helper Cell-Germinal Center B Cell Interaction Strength Regulates Entry into Plasma Cell or Recycling Germinal Center Cell Fate. Immunity. 2018;48(4):702-15.e4.AcknowledgementsWe thank the participants in the study, the radiology department at the Academic Medical Center (AMC) for lymph node sampling; the flow cytometry facility at the Hematology department at AMC, especially J.A. Dobber; and the core facility Cellular Imaging of the Amsterdam UMC, location AMC.Disclosure of InterestsDornatien Anang: None declared, Tamara H.Ramwadhdoebe: None declared, Janine Hahnlein: None declared, Bo van Kuijk: None declared, Smits Noortje: None declared, Krijn P. van Lienden: None declared, Mario Maas: None declared, Danielle Gerlag Employee of: Employee of UCB Pharma. UCB pharma was not involved in this study, Paul-Peter Tak Employee of: Employee of Candel therapeutics. Candel therapeutics was not involved in the study, Niek de Vries: None declared, Lisa van Baarsen: None declared.
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Cooley, Ian D., Kaitlin A. Read, Michael D. Powell, Chandra E. Baker, Bharath Sreekumar, Emily Martin, Jennifer E. Vaughn, and Kenneth J. Oestreich. "The Ikaros Family of Transcription Factors Regulates the Expression of the Transcriptional Repressor Bcl-6 in CD4+ T Cells." Blood 128, no. 22 (December 2, 2016): 1483. http://dx.doi.org/10.1182/blood.v128.22.1483.1483.
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Abstract Background: CD4+ T helper cells play critical roles in the regulation of pathogen-specific immune responses and immune tolerance. The formation of each individual T helper cell subset is dictated by the expression of a unique gene program. These gene programs are regulated by both the cytokine environment and cell-intrinsic, cytokine-responsive "lineage-defining" transcription factors, which imprint the conserved gene expression programs characteristic of a given T helper cell lineage. The transcriptional repressor Bcl-6 is one such factor, and has been identified as the lineage-defining transcription factor for the T follicular helper (TFH) cell subset. TFH cells participate in the generation of humoral immunity by providing help to B cells, which are responsible for the production of pathogen-neutralizing antibodies. Interestingly, Bcl-6 expression has also been implicated in the formation of CD4+ central memory T (TCM) cells, which play a critical role in long-term cell-mediated immunity. Recently, our laboratory has demonstrated that Bcl-6 expression can be induced in effector T helper 1 (TH1) cells in response to decreased interleukin 2 (IL-2) signaling. Consequently, TH1 cells are capable of upregulating Bcl-6-dependent TFH- and TCM-like gene programs, suggesting that these cells may be able to contribute to aspects of long-term humoral and cell-mediated immunity. Despite these insights, the upstream factor(s) that directly control the expression of Bcl-6 remain largely unknown. Preliminary RNAseq analysis indicated that the expression of members of the Ikaros family of zinc-finger transcription factors, which have been shown to play important roles in regulating gene expression during hematopoiesis, correlated with that of Bcl-6 in TH1 and TFH/TCM-like cells. As such, we hypothesized that Ikaros-family proteins may contribute to the regulation of Bcl-6 expression. Methods: Naïve CD4+ T cells isolated from the spleens and lymph nodes of 5-8 week old C57BL/6 mice were stimulated with α-CD3 and α-CD28 in TH1 polarizing conditions. Following the generation of TH1 cells, these cells were split into either high IL-2 conditions to maintain the TH1 phenotype or into low IL-2 conditions to induce the TFH/TCM-like phenotype. Total cellular RNA, total cellular protein, and chromatin samples were isolated for analysis. Results: In this study, we demonstrate that the Ikaros family members, Ikaros and Aiolos, are preferentially expressed in TFH/TCM-like cells when compared to TH1 cells. siRNA knockdown demonstrates that the expression of Bcl-6 correlates with that of Ikaros and/or Aiolos. To define the molecular mechanisms that lead to the aforementioned findings, we used chromatin immunoprecipitation (ChIP) assays to show that Ikaros and Aiolos directly bind to the Bcl-6 promoter region. Interestingly, co-immunoprecipitation experiments reveal that Ikaros and Aiolos physically interact, suggesting that they may act cooperatively to promote Bcl-6 expression. Finally, Ikaros and Aiolos siRNA experiments show that reduced expression of these transcription factors correlates with a reduction in the expression of a number of canonical TFH and TCM genes. Conclusion: Collectively, these results demonstrate that the Ikaros family members Ikaros and Aiolos are IL-2-sensitive transcription factors that positively regulate Bcl-6 expression and that of key TFH and TCM genes. These data support the possibility that Ikaros and Aiolos may be critical factors in the induction of the TFH and TCM cell types and thus, potentially, in the regulation of long-term humoral and cell-mediated immunity. Disclosures No relevant conflicts of interest to declare.
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Cusimano, Gina, Marita Chakhtoura, Bhavani Taramangalam, Jennifer Connors, Michele A. Kutzler, and Elias Haddad. "Adenosine deaminase-1 (ADA-1) induces maturation and skewing of cytokine and chemokine production in dendritic cells to improve adaptive immune responses." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 164.20. http://dx.doi.org/10.4049/jimmunol.208.supp.164.20.
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Abstract Dendritic cells (DCs) are critical mediators of antigen-specific immunity through their ability to present antigen and drive T cell differentiation into different effector subsets such as follicular helper T cells (TFH). TFH cells provide both physical and cytokine-mediated stimuli to B cells resulting in somatic hypermutation and class-switching of B cell receptors. Molecules that target TFH cells, such as adenosine deaminase-1 (ADA-1), would improve humoral immunity. We have previously demonstrated that co-delivery of plasmid-encoded adenosine deaminase with an HIV-1 envelope and SARS-CoV-2 DNA vaccines in vivo, enhanced both humoral and cellular responses. However, the mechanism by which ADA-1 is acting as an adjuvant remains to be elucidated. To this end, we treated monocyte-derived DCs from healthy human donors in vitro with recombinant ADA-1 protein and evaluated the expression of maturation markers, cytokines and chemokines. ADA-1-treated DCs had a significantly increased expression of CD40 and CD86 as well as HLA-DR compared to their unstimulated, immature counterparts. The level of co-stimulatory marker and HLA-DR expression on ADA-1-treated DCs was similar to that on LPS/IFN-γ-treated DCs, indicating ADA-1-mediated DC maturation. ADA-1-treated DCs also exhibited a significant increase in IL-6, IL-1β and CXCL13 expression. IL-6 is a key pro-TFH cytokine and IL-1β and CXCL13 may play a role in TFH cell differentiation, function, and proliferation. Ongoing studies are aimed to drive ADA-1 overexpression in DCs and evaluate effects on antigen presentation. Overall, elucidating the mechanism of ADA-1’s adjuvanticity will allow for its progression as a clinical adjuvant. This work was supported by funding to Dr. Elias Haddad from NIH 5RO1AI106482-01A and 1U19 AI128910-01.
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Ng, Siok-Bian, Shuangyi Fan, Shoa-Nian Choo, Michal Hoppe, Hoang Mai Phuong, Sanjay De Mel, and Anand D. Jeyasekharan. "Quantitative Analysis of a Multiplexed Immunofluorescence Panel in T-Cell Lymphoma." SLAS TECHNOLOGY: Translating Life Sciences Innovation 23, no. 3 (December 14, 2017): 252–58. http://dx.doi.org/10.1177/2472630317747197.
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Immunohistochemistry (IHC) provides clinically useful information on protein expression in cancer cells. However, quantification of colocalizing signals using conventional IHC and visual scores is challenging. Here we describe the application of quantitative immunofluorescence in angioimmunoblastic T-cell lymphoma (AITL), a peripheral T-cell lymphoma characterized by cellular heterogeneity that impedes IHC interpretation and quantification. A multiplexed immunofluorescence (IF) panel comprising T- and B-lymphocyte markers along with T-follicular helper (TFH) markers was validated for appropriate cellular localization in sections of benign tonsillar tissue and tested in two samples of AITL, using a Vectra microscope for spectral imaging and InForm software for analysis. We measured the percentage positivity of the TFH markers, BCL6 and PD1, in AITL CD4-positive cells to be approximately 26% and 45%, with 12% coexpressing both markers. The pattern is similar to CD4 cells within the germinal center of normal tonsils and clearly distinct from extragerminal CD4 cells. This study demonstrates the feasibility of automated and quantitative imaging of a multiplexed panel of cellular markers in formalin-fixed, paraffin-embedded tissue sections of a cellularly heterogenous lymphoma. Multiplexed IF allows the simultaneous scoring of markers in malignant and immune cell populations and could potentially increase accuracy for establishment of diagnostic thresholds.
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Zhen, Yu, and Shanshan Li. "Imbalance of Peripheral CD4+T Cell Subsets in Active Vitiligo." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 54.12. http://dx.doi.org/10.4049/jimmunol.196.supp.54.12.
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Abstract Accumulating studies have indicated that vitiligo is one kind of autoimmune diseases and CD4+T cells play important roles in the pathogenesis of vitiligo. However, there have been very limited papers concerning the profile of circulating CD4+T cell subsets in active vitiligo. To clarify this issue, we investigated the changes of peripheral Th1, Th2, Th17, Tfh and Tregs from 30 patients with active vitiligo. We found that compared with healthy controls, the percentages of circulating Th1 and Th17 were significantly increased, while the proportions of Th2 and Tregs showed no significant difference to healthy controls. Similar results were got in qualification of their corresponding transcription factors at mRNA level. In addition, the percentage of CD4+CXCR5+Tfh was significantly elevated in vitiligo patients. Compared with healthy controls, the expression level of IL-17A was significantly increased in sera of patients with active vitiligo, while the productions of IFN-γ, IL-4, TGF-β had no significant change. The imbalance observed between the effector and suppressor CD4+T cells in the current study suggests their involvement in the pathogenesis of vitiligo. Besides these changes of cellular immunity, increased Tfh indicates humoral immunity may also be responsible for development of vitiligo.
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Rodríguez, Marta, Ruth Alonso-Alonso, Laura Tomás-Roca, Socorro M. Rodríguez-Pinilla, Rebeca Manso-Alonso, Laura Cereceda, Jennifer Borregón, et al. "Peripheral T-cell lymphoma: molecular profiling recognizes subclasses and identifies prognostic markers." Blood Advances 5, no. 24 (December 20, 2021): 5588–98. http://dx.doi.org/10.1182/bloodadvances.2021005171.
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Abstract Peripheral T-cell lymphoma (PTCL) is a clinically aggressive disease, with a poor response to therapy and a low overall survival rate of approximately 30% after 5 years. We have analyzed a series of 105 cases with a diagnosis of PTCL using a customized NanoString platform (NanoString Technologies, Seattle, WA) that includes 208 genes associated with T-cell differentiation, oncogenes and tumor suppressor genes, deregulated pathways, and stromal cell subpopulations. A comparative analysis of the various histological types of PTCL (angioimmunoblastic T-cell lymphoma [AITL]; PTCL with T follicular helper [TFH] phenotype; PTCL not otherwise specified [NOS]) showed that specific sets of genes were associated with each of the diagnoses. These included TFH markers, cytotoxic markers, and genes whose expression was a surrogate for specific cellular subpopulations, including follicular dendritic cells, mast cells, and genes belonging to precise survival (NF-κB) and other pathways. Furthermore, the mutational profile was analyzed using a custom panel that targeted 62 genes in 76 cases distributed in AITL, PTCL-TFH, and PTCL-NOS. The main differences among the 3 nodal PTCL classes involved the RHOAG17V mutations (P < .0001), which were approximately twice as frequent in AITL (34.09%) as in PTCL-TFH (16.66%) cases but were not detected in PTCL-NOS. A multivariate analysis identified gene sets that allowed the series of cases to be stratified into different risk groups. This study supports and validates the current division of PTCL into these 3 categories, identifies sets of markers that can be used for a more precise diagnosis, and recognizes the expression of B-cell genes as an IPI-independent prognostic factor for AITL.
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Cho, Sung Hoon, Ariel L. Raybuck, Julianna Blagih, Edna Kemboi, Volker H. Haase, Russell G. Jones, and Mark R. Boothby. "Hypoxia-inducible factors in CD4+ T cells promote metabolism, switch cytokine secretion, and T cell help in humoral immunity." Proceedings of the National Academy of Sciences 116, no. 18 (April 15, 2019): 8975–84. http://dx.doi.org/10.1073/pnas.1811702116.
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T cell help in humoral immunity includes interactions of B cells with activated extrafollicular CD4+ and follicular T helper (Tfh) cells. Each can promote antibody responses but Tfh cells play critical roles during germinal center (GC) reactions. After restimulation of their antigen receptor (TCR) by B cells, helper T cells act on B cells via CD40 ligand and secreted cytokines that guide Ig class switching. Hypoxia is a normal feature of GC, raising questions about molecular mechanisms governing the relationship between hypoxia response mechanisms and T cell help to antibody responses. Hypoxia-inducible factors (HIF) are prominent among mechanisms that mediate cellular responses to limited oxygen but also are induced by lymphocyte activation. We now show that loss of HIF-1α or of both HIF-1α and HIF-2α in CD4+ T cells compromised essential functions in help during antibody responses. HIF-1α depletion from CD4+ T cells reduced frequencies of antigen-specific GC B cells, Tfh cells, and overall antigen-specific Ab after immunization with sheep red blood cells. Compound deficiency of HIF-1α and HIF-2α led to humoral defects after hapten-carrier immunization. Further, HIF promoted CD40L expression while restraining the FoxP3-positive CD4+ cells in the CXCR5+ follicular regulatory population. Glycolysis increases T helper cytokine expression, and HIF promoted glycolysis in T helper cells via TCR or cytokine stimulation, as well as their production of cytokines that direct antibody class switching. Indeed, IFN-γ elaboration by HIF-deficient in vivo-generated Tfh cells was impaired. Collectively, the results indicate that HIF transcription factors are vital components of the mechanisms of help during humoral responses.
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Cho, Sung Hoon, Ariel Raybuck, Edna Kemboi, Volker Haase, and Mark Robin Boothby. "Hypoxia-Inducible Factors (HIF) in CD4+ T cells promote metabolism, switch cytokine secretion, and T cell help in humoral immunity." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 186.17. http://dx.doi.org/10.4049/jimmunol.202.supp.186.17.
Full textAbstract:
Abstract T cell help in humoral immunity includes interactions of B cells with activated extrafollicular CD4+ and follicular T helper (Tfh) cells. Each can promote antibody responses but Tfh cells play critical roles during germinal center (GC) reactions. After re-stimulation of their antigen receptor (TCR) by B cells, helper T cells act on B cells via CD40 ligand and secreted cytokines that guide immunoglobulin class switching. Recent work showed that hypoxia is a normal feature of most GC, raising questions about molecular mechanisms governing the relationship between hypoxia and T cell help to antibody response. Hypoxia-inducible factors (HIF) are prominent among mechanisms that mediate cellular responses to limited oxygen but also are induced by lymphocyte activation. We now show that loss of HIF-1a and HIF-2a in CD4+ T cells compromised essential functions in help during antibody responses. HIF-1a depletion from CD4 T cells reduced frequencies of antigen-specific GC B cells, Tfh cells, and overall antigen-specific Ab. Compound deficiency of HIF-1a and HIF-2a intensified humoral defects after hapten-carrier immunization. Further, HIF promoted CD40L expression while restraining the FoxP3-positive CD4+ cells in the CCR5+ follicular regulatory (Tfr) population. Glycolysis increases T helper cytokine expression, and HIF was essential for stimulation of glycolysis in T helper cells via TCR or cytokine stimulation, as well as their production of cytokines that direct antibody class switching. Indeed, interferon-g elaboration by HIF-deficient in vivo-generated Tfh cells was impaired. Collectively, the results indicate that HIF transcription factors are vital components of the mechanisms of follicular help during humoral responses.
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Townsend, William M., Robert Marcus, Jon Salisbury, Deborah Yallop, Piers EM Patten, Andrea GS Buggins, and Stephen Devereux. "Multiparameter Microscopy Analysis of the Follicular Lymphoma Microenvironment and Normal Germinal Centers: In Vivo evidence That Follicular Helper T Cells Form Synapses with Neoplastic B Cells and Are Associated with Proliferation and Expression of Activation Induced Cytidine Deaminase." Blood 124, no. 21 (December 6, 2014): 144. http://dx.doi.org/10.1182/blood.v124.21.144.144.
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Abstract The tumor microenvironment plays a central role in the pathogenesis of follicular lymphoma (FL) and has been shown to influence prognosis. The biological basis for this and the contribution of individual cell types however, remain unclear. In this study we compared the cellular content and structure of neoplastic follicles in FL with their normal counterparts in reactive lymph nodes (LNs). We specifically focused on follicular helper T cells (TFH) which, in normal germinal centers (GCs), form immune synapses with antigen responsive B cells triggering B cell proliferation and expression of activation induced cytidine deaminase (AID), the enzyme required for somatic hypermutation and class switch recombination. This is of relevance because off-target AID activity is thought to play a role in generating the mutations that characterize progressive FL. A limitation of previous studies of the FL microenvironment is the use of either single parameter immunohistochemistry which fails to accurately define the complex populations of cells involved, or flow cytometry on disaggregated cells which results in the loss of architectural information. In this study we used multiparameter confocal immunofluorescent (IF) microscopy to investigate in vivo the phenotype, distribution and interaction of CD4+ T cells in FL and to determine to what extent these are similar to normal GCs. Confocal IF microscopy was performed on multiple sections of formalin fixed paraffin embedded LN biopsy specimens from 20 patients with untreated FL, comparison was made with reactive LNs (n=5) and chronic lymphocytic leukemia (CLL) LN biopsies (n=5). Each section was stained with a combination of up to 4 simultaneously applied primary antibodies against CD3, CD4, CD20, PD1, ICOS, BCL6, AID, and Ki67, and fluorescently labelled secondary antibodies. Microscopy was performed using a Nikon TiE fluorescent microscope equipped with A1R Si Confocal imaging system; images were analyzed using NIS software. Results show that CD4+ T cells in FL are mainly located in the inter-follicular regions but they were also identified within the follicles in all cases. Combination staining with anti-CD4, PD1, and ICOS revealed that 23% (95%CI 18-27) of CD4+ T cells within follicles co-express PD1 and ICOS consistent with a TFH phenotype which is significantly higher than in inter-follicular areas where only 5% (95% CI 3-7) of CD4+ cells had this phenotype (p<0.001). PD1+ ICOS+ T cells were positive for the transcription factor BCL6, further confirming the TFH phenotype. There was no significant difference in the proportion of CD4+ cells that were TFH in FL follicles and reactive LN GCs. In CLL cases, 54% of CD4+ cells expressed PD1 but only 9% co-expressed PD1 and ICOS, significantly lower than either FL follicles or GCs (p<0.001). Automated analysis of 3D z-stacks demonstrated a very close spatial relationship between proliferating tumor cells and TFH in FL with a mean of 42% (95%CI 35-48) Ki67+ tumor cells in direct contact with TFH cells. No association was seen between the extent of co-localization and histological grade. A similar pattern of co-localization of TFH cells next to proliferating B cells was also identified in the light zones of reactive GCs. Of note, we also identified features of synapse formation between TFH cells and proliferating tumor cells; TFH cells demonstrated projections that encompass the tumor cell with distortion of the T cell nucleus and increased CD4 and PD1 expression at sites of cell contact (Figure 1). These findings were similarly present in reactive GCs. Finally, AID was expressed in proliferating GC B cells and in proliferating tumor cells in FL. AID expressing cells were found to be in close contact with PD1+ T cells in both GCs and FL. Our findings show many parallels between the follicles of FL and normal GCs. In particular the proportion of CD4+ T cells with a TFH phenotype and their localization in direct contact with proliferating AID+ B cells were very similar. Of note, features of immune synapses were observed in both GCs and FL. Taken together, the data suggest that TFH cells have an important role in the pathogenesis of FL just as they are vital in the normal GC reaction. Interruption of this interaction is a potential therapeutic target. Figure 1 High power view (x60 zoom) of follicular lymphoma showing proliferating cells in close contact with TFH cells. Ki67 (red), PD1 (white), ICOS (green), DAPI (blue) Figure 1. High power view (x60 zoom) of follicular lymphoma showing proliferating cells in close contact with TFH cells. Ki67 (red), PD1 (white), ICOS (green), DAPI (blue) Disclosures No relevant conflicts of interest to declare.
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Watanabe, Masashi, Chiharu Fujihara, Chiang Y. Jeffrey, Sumeena Bhatia, and Richard J. Hodes. "Costimulatory pathways mediating T-dependent germinal center responses: distinct cellular requirements for CD40 and B7 costimulation." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 55.25. http://dx.doi.org/10.4049/jimmunol.196.supp.55.25.
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Abstract T cell-dependent (TD) germinal center (GC) and antibody responses require coordinated interactions of T cells with B cells and antigen-presenting dendritic cells (DCs). Although B7 and CD40 costimulatory pathways are critical for these responses, a comprehensive analysis of cell type-specific pathways has been hindered by the absence of models for conditional expression of B7 or CD40. Here we report generation of conditional knockout mice for both B7 and CD40, and the use of these lines together with conditional MHC class II (MHCII) knockouts and bone marrow chimeric strategies, to analyze pathways involved in TD GC and antibody responses. Our results indicate that MHCII-restricted recognition of both DCs and B cells is necessary for generation of antigen-specific TFH cells, GC B cells, and antibody response. Notably, the requirements for expression of B7 and CD40 were distinct, with B7 expression required on DCs but not on B cells, while CD40 was required on B cells but not DCs for generation of TFH cells, antigen-specific GC B cells, and antigen-specific class-switched antibody responses. These findings identify requirements for cell and costimulatory interactions in TD GC and antibody responses and support a unique model in which major costimulatory pathways function through interaction of T cells with distinct cell populations.
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Pallikkuth, Suresh, Anita Parmigiani, Sandra Y. Silva, Varghese K. George, Margaret Fischl, Rajendra Pahwa, and Savita Pahwa. "Impaired peripheral blood T-follicular helper cell function in HIV-infected nonresponders to the 2009 H1N1/09 vaccine." Blood 120, no. 5 (August 2, 2012): 985–93. http://dx.doi.org/10.1182/blood-2011-12-396648.
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Abstract The generation of Ab-secreting plasma cells depends critically on CD4 T-follicular helper (TFH) cells during the germinal center reaction. Germinal center TFH cells share functional properties with circulating CXCR5+ CD4 T cells, referred to herein as peripheral TFH (pTFH) cells. Because deficient Ab production and CD4 T-cell loss are recognized features of HIV infection, in the present study, we investigated pTFH cells in 25 HIV-infected patients on antiretroviral therapy. pTFH frequency was equivalent in patients and healthy controls (HCs), and these cells displayed a central memory phenotype. Sixteen patients and 8 HCs in this group were given a single dose of H1N1/09 influenza vaccine during the 2009 H1N1 influenza outbreak. In the vaccine responders (n = 8) and HCs, pTFH cells underwent expansion with increased IL-21 and CXCL13 secretion in H1N1-stimulated PBMC culture supernatants at week 4 (T2). These changes were not seen in vaccine nonresponders (n = 8). In coculture experiments, sorted pTFH cells supported HIN1-stimulated IgG production by autologous B cells only in vaccine responders. At T2, frequencies of pTFH were correlated with memory B cells, serum H1N1 Ab titers, and Ag-induced IL-21 secretion. Characterization of pTFH cells may provide additional insight into cellular determinants of vaccine-induced Ab response, which may have relevance for vaccine design.
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Higdon, Lauren, and Pamela Fink. "The role of germinal centers in T cell receptor revision (160.10)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 160.10. http://dx.doi.org/10.4049/jimmunol.186.supp.160.10.
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Abstract CD4+ T cells in Vβ5 transgenic mice become tolerant to an endogenous superantigen through either deletion or T cell receptor (TCR) revision. In the revision process, T cells downregulate surface Vβ5 expression and undergo RAG-mediated rearrangement and expression of endogenous TCRs. Revision occurs in germinal centers (GCs), suggesting that revising T cells may be follicular helper T cells (Tfh). We are studying whether revising T cells have a Tfh phenotype and whether GC interactions are required for revision. Preliminary data indicate that revising T cells have an RNA phenotype closely resembling that of Tfh and distinct from that of post-revision T cells. Studies on the intracellular and surface phenotype of revising and post-revision T cells are ongoing. The importance of GCs to TCR revision is being analyzed using SAP and CXCR5 null mice. SAP is required for prolonged interactions of B and T cells in the GC, and CXCR5 is required for cellular migration into the follicle. Analyses of mixed chimeras generated using CXCR5 null and wildtype bone marrow donors are ongoing. CXCR5 and SAP null mice have reduced numbers of post-revision T cells, but no reduction in revision intermediates. These results suggest that migration into the follicle and prolonged B-T cell interactions are both required for completion, but not initiation, of TCR revision.
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Vogelzang, Alexis, Helen McGuire, Jonathan Sprent, and Cecile King. "A fundamental role for Interleukin-21 in germinal center antibody responses (38.21)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 38.21. http://dx.doi.org/10.4049/jimmunol.182.supp.38.21.
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Abstract T cell help to B cells is a fundamental property of adaptive immunity, yet only recently have many of the cellular and molecular mechanisms of T cell help emerged. T follicular helper (TFH) cells are the CD4+ T helper cells that provide cognate help to B cells for high affinity antibody production in germinal centers (GC), and have recently been shown to give rise to lymphoid reservoirs of antigen specific memory T cells. TFH cells produce IL-21 and we have shown that IL-21 is necessary for GC formation. However the central role of IL-21 in GC formation reflected its effects on CD4+ T cells rather than on B cells. Furthermore, bone marrow chimeras confirm that IL-21R-deficient B cells are capable of mounting an effective IgG1 response to T dependent antigen. Using an antigen specific model where TCR transgenic CD4 T cells specific for the ovalbumin peptide were introduced into IL-21R-/- mice, we show that IL-21 responsiveness by T cells was important for optimal primary and secondary antibody responses. IL-21 also proved indispensable for affinity maturation of ova-specific antibodies in the GC. This study reveals a previously unappreciated role for TFH cells in the formation of the GC and isotype switching through a CD4+ T cell intrinsic requirement for responsiveness to IL-21.
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Stienne, Caroline, Aref Moshayedi, Elizabeth Chappell, Carl F. Ware, and John R. Sedy. "A cognate interaction between T cell-expressed BTLA and B cell-expressed HVEM regulates mucosal immunity in the gut." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 129.13. http://dx.doi.org/10.4049/jimmunol.202.supp.129.13.
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Abstract Mucosal immunity in the gut is achieved in part through cellular connections between lymphoid cells such as regulatory-T cells (Treg), T follicular helper cells (Tfh), T follicular regulatory cells (Tfr) and Germinal Center B cells (GC B). Btla (B and T Lymphocyte Attenuator) is a receptor mainly expressed on B and T cells that is activated by its ligand Hvem (Herpesvirus entry mediator; Tnfrsf14) to inhibit cellular activation. However, the role of these specific immune checkpoints in the regulation of mucosal immunity in the gut is still unknown. In mice containing genetic ablation of Btla in T cells, we observed an increased frequency of Tfh and GC B cells in Peyer’s Patches (PP), and a decreased frequency of Treg and Tfr cells in these tissues. Interestingly, in mice with a B-cell-specific deletion of the Btla ligand Tnfrsf14 (Hvem), we observe similar increases in GC B cells and Tfh cells and decreased in Treg. Moreover, these mice are characterized by an increase of mucosal IgA bound to bacteria in fecal pellets, indicating a functional outcome of Btla regulation of the GC. Finally, treating wild-type mice with an antibody agonist for Btla increases the frequency of regulatory T cells in PP demonstrating the potential therapeutic effect of activating Btla inhibitory signaling in mucosal immunity. Together, we show that T cell-expressed Btla interacts with B cell-expressed Hvem to regulate GC responses in Peyer’s Patches. A disruption of the balance effector T cell/regulatory T cell is responsible for many inflammatory autoimmune diseases. It will be crucial to understand the role of Btla and its ligand in these populations in mucosal tissues to understand how immunity is regulated, and to develop potential novel therapeutics to treat disease.
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Vaca, Alicia, Nikolaos Ioannou, Mariela Sivina, Elisavet Vlachonikola, Karen Clise-Dwyer, Ekaterina Kim, Dan Li, et al. "Expansion of T Follicular Helper Cells in NLC Co-Cultures Reinforces the Concept of Co-Evolution of CLL and Supportive T Helper Cell Clones." Blood 138, Supplement 1 (November 5, 2021): 3716. http://dx.doi.org/10.1182/blood-2021-151351.
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Abstract CLL cells proliferate in secondary lymphatic tissues where the CLL cells interact with T cells, monocyte-derived nurselike cells and mesenchymal stromal cells, collectively referred to as the tissue microenvironment. The CLL lymph node morphology with proliferation centers resembles normal B cell follicles, suggesting that mechanisms regulating the expansion of antigen-selected normal B cells during the germinal center (GC) reaction also regulate CLL cell expansion. Normal GC reactions require specialized T follicular helper (Tfh) cells, which provide T cell help to antigen-stimulated B cells. Another important T cell subset are Tregs which regulate immune tolerance and homeostasis. NLC co-culture have been used to dissect cellular and molecular interactions between CLL cells and the lymph node microenvironment in vitro. To gain insight into the role of T cell subsets in CLL, we utilized the NLC model to characterize T cell subsets and their dynamics in NLC co-cultures. We quantified CD4 + and CD8 + T cells in co-cultures from 18 different patients, observing that CD4 + T cell counts remained stable over time (449±62 at baseline to 443±80 cells/µl after 14 days). In contrast, numbers of CD8 + T cells declined from 180±42 cells/µl to 98±16 cells/µl on day 14 (p<0.05). T helper cell subset analyses in 28 different samples revealed an increase in Tfh cells (from 1.7±0.3% to 6.0±0.9%, p<0.001) and Tregs (from 3.3±0.5% to 9.6±1.7%, p<0.001) after 14 days. In contrast, Th17 cell frequency remained unchanged. PD-1 expression levels on Tfh cells were tested to distinguish memory (PD-1 +) from germinal (PD-1 +++) Tfh cells. NLC co-culture resulted in an increase of germinal (0.2±0.1% to 2.4±0.3%, p<0.0001) and memory Tfh cells (10.2±1.5% to 18.8±1.7%, p<0.0001). In addition, germinal Tfh cells expressed high levels of BCL6 (39.4±4.4 to 179.0±5.9, n=8, p<0.001), ICOS (119.0±68.0 to 574.0±154.0, n=6, p<0.05), and IL-21 after co-culture (10.3±2.6% to 29.5±6.5%, p<0.01, n=12). In contrast, CD40L was downregulated on memory Tfh cells from 24.4±8.6% to 8.7±2.4% (p=0.05, n=9). Tregs showed an increase of TGFß levels (4.3±1.4% to 25.3±8.5%, p<0.05), and IL-10 expression (2.2±0.4% to 7.4±2.0%, p<0.05, n=12), indicating activation during co-culture. Interestingly, NLC co-cultures also induced Ki-67 in germinal (13.0±4.9% to 39.5±5.7%, p<0.001) and memory Tfh cells (1.7±0.3% to 13.0±4.9%, p<0.05), and Tregs (2.5±0.6% to 18.0±3.3%, p<0.001, n=13). To examine whether the expansion of Tfh and Treg cells in NLC co-cultures correlated with changes in T cell receptor (TR) gene repertoire we performed TR beta chain immunosequencing. Using the beta-binomial method, we analyzed the abundance of TR gene rearrangements, identifying clonotypes that were differentially abundant at 14 days. Next, to assess the similarity/overlap between the CD4 + TR gene repertoires at baseline and after co-culture, we utilized the Morisita overlap index (MOI). We found that the 6 samples with increased clonality had MOIs ranging from 0.12 to 0.53. Then, we compared the top 20 most expanded CDR3 sequences from each sample with low MOI with CDR3 sequences obtained in previous TR immunoprofiling studies from untreated CLL patients. Interestingly, we found numerous shared TR beta CDR3 sequences between NLC co-cultures and unrelated CLL patient samples. Furthermore, we correlated the Tfh expansion at 14 days normalized to baseline with MOI, a significant indirect correlation was noted (R 2=0.5, p=0.02, n=10). Interactions between CLL cells and Tfh or Tregs were evaluated in six LN CLL samples using multispectral microscopy. High magnification imaging and 3D Z-stack reconstructions revealed that there was a close spatial relationship between clusters of Ki-67 +CLL and Tfh cells within CLL LNs. In contrast, FOXP3 +CD4 + cells were generally found in cell groups in close proximity to other CD4 + cells. We next assessed whether the ICOS +CD4 + cell expansion was correlated with CLL proliferation and found a correlation between the percentage of ICOS +CD4 + cells with proliferating CLL cells in situ (R 2=0.75, p=0.03, n=6), whereas, no correlation was found with FOXP3 +CD4 + cell frequency. Collectively, these data provide new insight into the cellular and molecular cross-talk between CLL and T cell subsets, resulting in clonal expansion of T helper cells and interaction of Tfh cells with proliferating CLL cells opening new avenues for therapeutic targeting. Disclosures Ferrajoli: Janssen: Other: Advisory Board ; AstraZeneca: Other: Advisory Board, Research Funding; BeiGene: Other: Advisory Board, Research Funding. Wierda: Oncternal Therapeutics, Inc.: Research Funding; Sunesis: Research Funding; Gilead Sciences: Research Funding; GSK/Novartis: Research Funding; Acerta Pharma Inc.: Research Funding; Genentech: Research Funding; Karyopharm: Research Funding; KITE Pharma: Research Funding; Juno Therapeutics: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Cyclacel: Research Funding; Miragen: Research Funding; Loxo Oncology, Inc.: Research Funding; Janssen: Research Funding; Xencor: Research Funding; AstraZeneca: Research Funding; Genzyme Corporation: Consultancy; AbbVie: Research Funding. Patten: ABBVIE: Honoraria; ASTRA ZENECA: Honoraria; GILEAD SCIENCES: Honoraria, Research Funding; JANSSEN: Honoraria; NOVARTIS: Honoraria; ROCHE: Research Funding. Burger: Novartis: Other: Travel/Accommodations/Expenses, Speakers Bureau; Beigene: Research Funding, Speakers Bureau; Pharmacyclics LLC: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Gilead: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; AstraZeneca: Consultancy; Janssen: Consultancy, Other: Travel/Accommodations/Expenses, Speakers Bureau.
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Wang, Lifang, Yu Zhang, Mingqin Zhu, Jiachun Feng, Jinming Han, Jie Zhu, and Hui Deng. "Effects of Follicular Helper T Cells and Inflammatory Cytokines on Myasthenia Gravis." Current Molecular Medicine 19, no. 10 (October 15, 2019): 739–45. http://dx.doi.org/10.2174/1566524019666190827162615.
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Background: Myasthenia gravis (MG) is an autoimmune disorder mediated by antibodies against the acetylcholine receptors (AChR) of the skeletal muscles. An imbalance in various T helper (Th) cells, including Th1, Th2, Th17, Th22 and follicular helper T (TFH) cells, has been found associated with immunological disturbances. Objective: In this study, we aim to investigate the role of the Th cells in peripheral blood of MG patients. Materials and Methods: A total of 33 MG patients and 34 age matched controls were enrolled in this study. Peripheral blood mononuclear cells (PBMCs) were isolated using Ficoll-Paque density gradient centrifugation assay. The proportion of TFH cells in PBMC were analyzed using flow-cytometry assay by determining the levels of cellular markers CD4, CXCR5, CD45RO, CD45RA and ICOS and PD-1. The levels of IFN-γ, IL-4, IL-17 and IL-21 in serum were analyzed by Cytometric Bead Array. The serum IL-22 level was analyzed by ELISA. Results: The frequency of TFH cells in PBMCs was higher than those in healthy subjects and correlated to the severity of MG patients. The levels of pro-inflammatory cytokines IFN-γ, IL-17 and IL-21 were elevated in the serum of MG patients, while there were no significant differences regarding the levels of IL-4 and IL-22 between MG patients and control subjects. Conclusion: Our findings suggest that Th cells and their cytokines balance of MG patients are involved in the clinical condition or severity of MG disease.
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Furtado, Raquel M., Gregoire Lauvau, and Johanna P. Daily. "Circulating memory CD4 T follicular helper cell subsets correlate with clinical immunity against human malaria." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 125.23. http://dx.doi.org/10.4049/jimmunol.198.supp.125.23.
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Abstract Malaria remains a global burden with over 200 million infections and half a million deaths annually. While studies in human and surrogate mouse models reveal that B cells and CD4 T cells are essential, it is not known if and how sterilizing immunity against malaria may be achieved. Residents of endemic areas develop clinical immunity to Plasmodium falciparum over time yet protection is partial and requires repeated exposures. Herein we conducted a 2 year longitudinal study on patients with mild malaria in a hyperendemic region in Malawi. We categorized patients with a high number and short interval between reinfections (‘susceptible’) and with a low number and longer interval between reinfections (‘protected’). We hypothesized that clinical immunity correlates with the presence of specific immune cell subsets in protected versus susceptible patients. We conducted comprehensive cellular profiling on patient PBMCs, isolated during infection, by mass cytometry and a panel of 33 markers. We examined the frequency and activation of 40 immune cell subsets by unsupervised clustering analysis and discovered an expansion of CXCR3lo memory CD4T follicular helper cells (Tfh) in protected patients compared to susceptible patients. Importantly, with an in vitro antibody dependent opsonization assay we found increased phagocytosis of P. falciparum merozoites with plasma from protected versus susceptible patients, correlating CXCR3lo memory Tfh cell frequency with enhanced humoral responses. We speculate that CXCR3lo memory Tfh cells are critical for lasting protective responses against malaria in humans and may be essential for an efficacious future vaccine.
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Hale, J. Scott, Andrew Baessler, Camille L. Novis, Zuolian Shen, Jelena Perovanovic, Mark Wadsworth, Linda M. Sircy, Malia Harrison-Chau, Katherine E. Varley, and Dean R. Tantin. "Tet2-mediated programing balances T follicular helper cell and T helper 1 cell differentiation." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 112.24. http://dx.doi.org/10.4049/jimmunol.208.supp.112.24.
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Abstract The differentiation of CD4+ T cell subsets in response to infection has been studied extensively, however the epigenetic programs that regulate these processes remain poorly understood. Active demethylation by tet methylcytosine dioxygenases of CpG dinucleotides within DNA is a key component of epigenetic programing that promotes lineage specific gene expression and contributes to cellular differentiation and function. Here we report that Tet2 acts to restrict the differentiation of T follicular helper (Tfh) cells in CD4+ T cells responding to viral infection. Using an adoptive transfer model of virus-specific CD4+ cells we found that Tet2-deficient CD4+ T cells skew away from the Th1 lineage and instead preferentially differentiate into highly functional germinal center (GC) Tfh cells that provide enhanced help for B cell responses. We found that the impact of Tet2-mediated programing on CD4+ T cell differentiation is cell intrinsic and the shift in lineage differentiation occurs as early as 2 days post infection. Using genome-wide expression, DNA methylation and transcription factor binding analyses, we found that Tet2 coordinates with multiple transcription factors to mediate the demethylation and expression of their target genes following activation. Our findings establish Tet2 as an important regulator of Tfh cell differentiation and reveal pathways that could be targeted to enhance GC responses against infectious disease. Supported by grants from NIH (R01 AI137238 to J.S.H., T32 AI055434 to L.M.S., and T32 AI138945 to A.B.
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Wang, Ying-Ting, Sararat Hattakam, Matthew Perry Young, Jose Angel Regla-Nava, and Sujan Shresta. "Monocytes and macrophages limit systemic infection and modulate the CD4 T cell response during Zika virus infection in mice." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 140.5. http://dx.doi.org/10.4049/jimmunol.202.supp.140.5.
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Abstract Monocytes and macrophages are antiviral innate immune effector cells that also serve as cellular hosts of Zika virus (ZIKV). To investigate the precise role of monocytes and macrophages during ZIKV infection in vivo, monocytes and macrophages were depleted with clodronate liposomes before ZIKV infection in wild-type C57BL/6 mice, and viral burden and ZIKV-specific immune responses were assessed. Chlodronate liposometreated mice had higher level of ZIKV RNA in the serum and spleen relative to control liposome-treated mice at early time points after infection. At later time points after infection, chlodronate liposome-treated mice developed an impaired ZIKV-specific Th1 response in terms of both magnitude and quality, whereas they exhibited enhanced Tfh, germinal center B cell, plasma cell, and neutralizing antibody responses as compared to control liposome-treated mice. These data indicate that monocytes and macrophages limit ZIKV dissemination and regulate the balance between Th1 versus Tfh responses during ZIKV infection. Thus, monocytes and macrophages contribute to both the innate control of ZIKV infection and regulation of the adoptive immune response.
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Zhang, Biyan, Elise Liu, Jake A. Gertie, Julie Joseph, Lan Xu, Elisha Y. Pinker, Daniel A. Waizman, et al. "Divergent T follicular helper cell requirement for IgA and IgE production to peanut during allergic sensitization." Science Immunology 5, no. 47 (May 8, 2020): eaay2754. http://dx.doi.org/10.1126/sciimmunol.aay2754.
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Immunoglobulin A (IgA) is the dominant antibody isotype in the gut and has been shown to regulate microbiota. Mucosal IgA is also widely believed to prevent food allergens from penetrating the gut lining. Even though recent work has elucidated how bacteria-reactive IgA is induced, little is known about how IgA to food antigens is regulated. Although IgA is presumed to be induced in a healthy gut at steady state via dietary exposure, our data do not support this premise. We found that daily food exposure only induced low-level, cross-reactive IgA in a minority of mice. In contrast, induction of significant levels of peanut-specific IgA strictly required a mucosal adjuvant. Although induction of peanut-specific IgA required T cells and CD40L, it was T follicular helper (TFH) cell, germinal center, and T follicular regulatory (TFR) cell–independent. In contrast, IgG1 and IgE production to peanut required TFH cells. These data suggest an alternative paradigm in which the cellular mechanism of IgA production to food antigens is distinct from IgE and IgG1. We developed an equivalent assay to study this process in stool samples from healthy, nonallergic humans, which revealed substantial levels of peanut-specific IgA that were stable over time. Similar to mice, patients with loss of CD40L function had impaired titers of gut peanut-specific IgA. This work challenges two widely believed but untested paradigms about antibody production to dietary antigens: (i) the steady state/tolerogenic response to food antigens includes IgA production and (ii) TFH cells drive food-specific gut IgA.
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Watanabe, Masashi, and Richard Hodes. "Cellular and molecular basis of Ag-specific and Ag-nonspecific T-dependent antibody responses in vivo (IRC8P.447)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 129.11. http://dx.doi.org/10.4049/jimmunol.194.supp.129.11.
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Abstract Although B7 is essential for T-dependent Ag-specific Ab production, little is known about cell type specific role of B7 for these responses. Utilizing B7cKO mice, the cell type specific roles of B7 costimulation for T-dependent GC and Ab responses were analyzed. Upon NP-OVA/Alum immunization, NP-specific IgG1 production was profoundly defective in mice lacking B7 expression on DC (DC-B7KO) but was intact in mice lacking B7 on B cells (BC-B7KO). Consistent with this, NP-binding GC B cells and Ag-specific CD4+ T cell expansion were not observed in DC-B7KO. Surprisingly, however, GC formation and total numbers of GC B and TFH were undiminished in DC-B7KO; whereas BC-B7KO showed reduction of total number of GC B and TFH despite normal numbers of NP-binding GC B. These results demonstrate that B7 on DC but not B cells is critical for Ag-specific CD4+ T cell expansion and IgG1 production. In contrast, a distinct pathway dependent upon B7 on B cells but not DC supported apparently Ag-nonspecific GC response. Of interest, MHCII on B cells but not on DC was required for Ag-nonspecific GC response, indicating that cognate T-B but not T-DC interaction was responsible for eliciting Ag-nonspecific GC response. Our study revealed a previously unappreciated B7-dependent Ag-nonspecific Ab production pathway and demonstrated distinct cellular and molecular pathways for Ag-specific and Ag-nonspecific components of T-dependent Ab responses.
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Hapgood, Greg, Anja Mottok, Graham W. Slack, Randy D. Gascoyne, Christian Steidl, Kerry J. Savage, and Andrew P. Weng. "Flow Cytometric Characterization of 129 Cases of Peripheral T Cell Lymphoma Not Otherwise Specified (PTCL NOS) and Angioimmunoblastic T Cell Lymphoma (AITL)." Blood 126, no. 23 (December 3, 2015): 2667. http://dx.doi.org/10.1182/blood.v126.23.2667.2667.
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Abstract Background: Peripheral T cell lymphoma not otherwise specified (PTCL NOS) and angioimmunoblastic T cell lymphoma (AITL) together comprise approximately half of all peripheral T cell lymphomas. Malignant T cells in AITL and in a subset of PTCL-NOS exhibit a phenotype mimicking that of normal T-follicular helper (TFH) cells. Immunohistochemical (IHC) studies performed on paraffin-embedded tissues are a mainstay of diagnostic histopathology, but can be difficult to interpret when the malignant T cells show limited cytological atypia and when there are abundant infiltrating reactive T cells. Flow cytometry represents an alternate means to define the cellular immunophenotype, but requires access to single cell suspensions of viable tumor cells. Flow cytometry has certain additional benefits over IHC including highly quantitative measurement of multiple antigens simultaneously and statistical power afforded by analyzing tens of thousands of individual cells. We report here immunophenotypic characterization of a large cohort of cases of PTCL NOS and AITL using a 12-color flow cytometry assay and correlation of immunophenotypic features with clinical outcomes. Methods: Cases of PTCL-NOS and AITL spanning a 24 year period (1990-2014) for which viably frozen cell suspensions from diagnostic lymph node biopsies were available were identified within the British Columbia Cancer Agency (BCCA) lymphoma database. Cryopreserved cell suspensions were thawed and stained with a 12-color panel including 11fluorochrome-conjugated antibodies against lineage (CD45, CD19, CD3, CD4, CD8), pan-T cell (CD2, CD5, CD7), and TFH cell (CD10, CD279, CXCR5) markers, plus DAPI for gating of live cells. Flow cytometric data was acquired on a Becton Dickinson FACSAria3 instrument as part of a sorting experiment to isolate tumor cell subpopulations. Data was analyzed by conventional gating and bivariate plot display using FlowJo software and correlated with clinical outcome data. Results: 74 cases of PTCL-NOS and 55 cases of AITL were analyzed. The median age at diagnosis was 57 years (y) for PTCL NOS (male:female 1.6) and 75 y for AITL (male:female 1.0). The median follow up for living patients was 5.15 y. The median specimen viability was 36.5% (range 0.8-89.3%) and median specimen tumour content was 64.3% of viable events (range 0.98-91.8%). Aberrant T cell immunophenotypes were identified in 50 of 74 cases (68%) of PTCL NOS and 36 of 55 cases (65%) of AITL. Five specimens had more than one identifiable immunophenotypically aberrant T cell population. For the 50 PTCL NOS cases with an aberrant immunophenotype, 31 (62%) demonstrated loss of CD3 and 42 (84%) demonstrated loss of CD7. About half of cases were CD4+CD8- (27, or 54%) including 11 (22%) that exhibited a TFH-like phenotype (positive for at least 2 of the 3 assayed TFH markers), while the remaining were CD4-CD8- (23, or 46%). TFH-like cells were also identified in 11 of 24 (46%) cases lacking an aberrant T cell immunophenotype. For the 36 AITL cases with an aberrant immunophenotype, 21 (58%) demonstrated loss of CD3 and 29 (80%) demonstrated loss of CD7. The majority of cases were CD4+ (30, or 83%) including 21 (58%) that exhibited a TFH-like phenotype, while the remaining were either CD8+ (4, or 11%) or CD4-CD8- (2, or 6%). TFH-like cells were also identified in 7 of 19 (37%) cases lacking an aberrant T cell immunophenotype. Similar to other patient cohorts, the 5 y PFS and 5 y OS was 21% and 40%, respectively, for PTCL NOS and 17% and 28%, respectively, for AITL. The presence of an aberrant phenotype, CD3 status, and CD4/CD8 status were not associated with prognosis in either PTCL subtype. A preliminary analysis suggests loss of CD7 expression in PTCL NOS is associated with an inferior outcome. Analysis of archival material and exploration in a validation cohort is ongoing. Discussion: An aberrant population of varying abundance was detected in >65% of specimens for PTCL NOS and AITL. The aberrant immunophenotype in PTCL NOS was evenly split between CD4+CD8- and CD4-CD8- cases. Interestingly, nearly half of CD4+ cases showed evidence of TFH-like differentiation, possibly corresponding to the TFH-like variant of PTCL NOS. The aberrant immunophenotype in AITL was typically CD4+ and often with co-expression of TFH-associated markers. Loss of CD7 and CD3 were the most common abnormalities. Loss of CD7 may demonstrate a poor-risk group of patients with inferior outcomes in PTCL NOS. Disclosures Savage: Seattle Genetics: Honoraria, Speakers Bureau; BMS: Honoraria; Infinity: Honoraria; Roche: Other: Institutional research funding.
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Olatunde, Adesola C., Patrice N. Mimche, Spencer O. Seely, Taryn P. Stewart, and Tracey J. Lamb. "Ephrin B receptor tyrosine kinase ligands modulate the germinal center reaction and control humoral immune responses to malaria." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 190.29. http://dx.doi.org/10.4049/jimmunol.202.supp.190.29.
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Abstract Malaria remains a global health priority causing half a million deaths annually. Protective antibody responses that can control the Plasmodium parasites that cause malaria are an essential component of naturally acquired immunity and develop after years of continuous exposure to Plasmodium parasites. The protective humoral response is short-lived and tends to wane in the absence of parasite re-infections. The cellular and molecular mechanisms that prevent the development of long-lived humoral immunity against malaria remain poorly understood. Recently, ephrin B1, a ligand for the Eph B receptor tyrosine kinase subfamily, was shown to be involved in T follicular helper (Tfh) cell recruitment, retention and contact-dependent interaction with germinal center (GC) B cells, key processes in the production of efficacious antibody responses. We hypothesize that EphB/EphrinB signaling pathway is required for the development of Plasmodium humoral responses. Using a non-lethal P. yoelii XNL infection model, we observed an upregulation in the expression of Ephrin B on both GC B cell and Tfh cells at the peak of the infection in wild type mice. Selective deficiency of Ephrin B1/B2 on B cells (CD19cre+ Ephrin B1/B2fl/fl mice) led to lethality in some mice infected with an otherwise non-lethal P. yoelii XNL infection. On the other hand mice that lack the expression of Ephrin B1/B2 on T cells (CD4cre+ Eprhin B1/B2fl/fl mice) were able to control P. yoelii XNL infection. Our data show a requirement for Ephrin B1/B2 signaling on B cells for an effective contact-dependent interaction with Tfh cells and for optimal antibody responses during Plasmodium infection.
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Kwak, Kihyuck, Nicolas Quizon, Haewon Sohn, Avva Saniee, Javier Manzella-Lapeira, Prasida Holla, Joseph Brzostowski, et al. "Intrinsic properties of human germinal center B cells set antigen affinity thresholds." Science Immunology 3, no. 29 (November 30, 2018): eaau6598. http://dx.doi.org/10.1126/sciimmunol.aau6598.
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Protective antibody responses to vaccination or infection depend on affinity maturation, a process by which high-affinity germinal center (GC) B cells are selected on the basis of their ability to bind, gather, and present antigen to T follicular helper (Tfh) cells. Here, we show that human GC B cells have intrinsically higher-affinity thresholds for both B cell antigen receptor (BCR) signaling and antigen gathering as compared with naïve B cells and that these functions are mediated by distinct cellular structures and pathways that ultimately lead to antigen affinity– and Tfh cell–dependent differentiation to plasma cells. GC B cells bound antigen through highly dynamic, actin- and ezrin-rich pod-like structures that concentrated BCRs. The behavior of these structures was dictated by the intrinsic antigen affinity thresholds of GC B cells. Low-affinity antigens triggered continuous engagement and disengagement of membrane-associated antigens, whereas high-affinity antigens induced stable synapse formation. The pod-like structures also mediated affinity-dependent antigen internalization by unconventional pathways distinct from those of naïve B cells. Thus, intrinsic properties of human GC B cells set thresholds for affinity selection.