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1
Chen, Junwei, Junxia Li, Huiying Gao, Caihong Wang, Jing Luo, Zhiqin Lv, and Xiaofeng Li. "Comprehensive Evaluation of Different T-Helper Cell Subsets Differentiation and Function in Rheumatoid Arthritis." Journal of Biomedicine and Biotechnology 2012 (2012): 1–6. http://dx.doi.org/10.1155/2012/535361.
Повний текст джерелаАнотація:
Rheumatoid arthritis (RA) is the most common autoimmune disorder. Loss of Th1/Th2 and Th17/Treg balance has been reported in several inflammatory autoimmune diseases. This study was to investigate Th1, Th2, Th17, and Treg differentiation and related cytokines in RA patients. The frequencies of Th1, Th2, Th17, and Treg cells in peripheral blood of RA patients (n=76) and healthy controls (n=18) were determined by flow cytometry. Eight serum cytokines were analyzed using cytometric bead array. The results demonstrated that RA patients exhibited increased peripheral Th1/Th17 cells and Th1/Th17-related cytokines. However, Th1 cells only reached significant difference at advanced stage, but Th17 at all stages, suggesting more important roles in Th17 cells. For Th2 and Treg cells, there was a different function pattern in RA progression. Although with the increase of DAS28 score, Th2 cell experienced some degree of decrease in RA patients, no significant difference was observed. IL-4 and IL-10 showed a significant increase in RA patients. These indicated that Th2 cells might exert immunosuppression effects mainly by secreting cytokines. Treg cells were found significantly decreased in RA patients, but no difference was observed in TGF-βexpression, indicating a cell-cell interaction pattern in Treg cell.
2
Damsker, Jesse M., Anna M. Hansen, and Rachel R. Caspi. "Th1 and Th17 cells." Annals of the New York Academy of Sciences 1183, no. 1 (January 2010): 211–21. http://dx.doi.org/10.1111/j.1749-6632.2009.05133.x.
Повний текст джерела
3
FANG, Yujiang, Shiguang YU, and Helen MULLEN. "Differential sensitivity of Th1, Th2 and Th17 cells to Fas-mediated apoptosis (47.15)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 47.15. http://dx.doi.org/10.4049/jimmunol.182.supp.47.15.
Повний текст джерелаАнотація:
Abstract In response to T cell receptor crosslinking, naïve CD4+ T cells can differentiate into three major subsets, Th1, Th2 and Th17 cells. Th17 cells play an important role in the pathogenesis of autoimmune diseases, but little is known about the regulation of apoptosis in Th17 cells. This study was undertaken to directly determine and compare the sensitivity of in vitro polarized Th1, Th2 and Th17 cells to Fas-mediated apoptosis and to determine if the anti-apoptotic molecule FLIP could inhibit apoptosis of each of the three subsets. Using several different methods, the order of sensitivity of T cell subsets to Fas-mediated apoptosis is: Th1>Th17>Th2. The greater sensitivity of Th17 cells compared to Th2 cells correlated with their higher expression of FasL. The decreased sensitivity of Th17 compared to Th1 cells correlated with higher expression of FLIP by Th17 cells. Transgenic overexpression of FLIP in T cells protected all three subsets from Fas-mediated apoptosis. Using splenocytes from IFNγ-/- mice, Fas-mediated apoptosis of T cells activated under Th1 polarization-inducing conditions were shown to be dependent on IFN-γ, while Fas-mediated apoptosis of Th17 and Th2 cells was IFN-γ independent. These findings provide new knowledge for understanding how survival of different subsets of T cells is regulated. This information might be useful for the design of new strategies to treat autoimmune diseases (NIH DK35527).
4
Banuelos, Jesus, and Nick Lu. "Distinct apoptotic machinery and selective gene regulation by glucocorticoids in Th17 cells (P1294)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 119.6. http://dx.doi.org/10.4049/jimmunol.190.supp.119.6.
Повний текст джерелаАнотація:
Abstract Glucocorticoids (GCs) are extensively used in the treatment of inflammatory disorders and surprisingly, are ineffective in suppressing Th17 responses. We sought to determine the mechanisms underlying the insensitivity of Th17 cells to GCs. We found that in vitro polarized murine Th1 and Th2 cells, but not Th17 cells, were sensitive to GC-induced apoptosis as determined by various apoptotic markers such as annexin-V staining. At the mRNA level, GCs suppressed IL-4 and IFN-γ, and unexpectedly IL-22 but not IL-17 (A and F). Despite the distinct GC responses, Th1, Th2, and Th17 cells showed similar levels of GC receptor (GR) isoforms. Using PCR array to survey 84 genes involved in apoptosis, we found significant differences in the apoptotic machinery between Th1 and Th17 cells. Th17 cells showed increased expression of anti-apoptotic survivin and Bfl-1 whereas Th1 cells showed increased expression of pro-apoptotic Bim, Fas ligand, caspase 1, and death receptor 5. GCs induced Bim in both Th1 and Th17 cells while the same treatment decreased the expression of Nod1 and Bcl-xL in Th1 but not Th17 cells. Altered apoptotic machinery and differences in genes regulated after GC treatment may underlie the inability of GCs to induce apoptosis in Th17 cells. These studies on the mechanisms underlying the selective insensitivity of Th17 cells to GCs may provide a basis for improved treatment regimens for severe asthma and other Th17-mediated disorders.
5
Nelson, Michelle, Stefanie Bailey, Logan Huff, Sreenath Kundimi, and Chrystal Paulos. "Multifunctional CD26hi Th17 cells eradicate large human tumors (TUM2P.902)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 71.26. http://dx.doi.org/10.4049/jimmunol.192.supp.71.26.
Повний текст джерелаАнотація:
Abstract Human CD4+ T cells differentiate into multiple effector subsets, but their distinct roles in anti-tumor immunity remain elusive. CD4+ T cell subsets enriched from bulk human CD4+ T cells [Th1 (CXCR3+), Th2 (CCR4+), and Th17 (CCR6+ or CD26hi)] were stimulated with anti-CD3 beads bearing agonists to either CD28 or ICOS and were then engineered with a chimeric antigen receptor that recognizes human mesothelioma. In vitro, ICOS costimulation proved superior to CD28 for augmenting the function of human Th1, Th2, CCR6+ Th17 and CD26hi Th17 cells, as indicated by elevated production of IFN-γ, IL-4 and IL-17A, respectively. Moreover, CD26hi Th17 cells possessed strikingly enhanced polyfunctionality compared to Th1, Th2 or CCR6+ Th17 cells, as demonstrated by their heightened capacity to co-secrete IL-17A, IFN-γ, IL-22, IL-2, and TNF-α simultaneously. Compared to other enriched T cell subsets, a greater percentage of CD26hi Th17 cells exhibit an effector memory phenotype. In vivo, CD26hi Th17 cells more efficiently reconstituted immunodeficient hosts and persisted long-term. Furthermore, CD26hi Th17 cells possessed a superior ability to kill large human tumors (>150mm2) when infused into mice compared to Th1, Th2 or CCR6+ Th17 cells. These results suggest that the generation of multifunctional, long-lived human Th17 populations could be instrumental to the design of novel, effective T cell-based cancer therapies.
6
Liu, Houpu, Ting Feng, Qingjie Li, Wenbo Zhang, Suxia Yao, Charles Elson та Yingzi Cong. "TGFβ converts Th1 cell into Th17 cells through stimulation of Runx1 expression under inflammatory conditions in intestines (MUC2P.819)". Journal of Immunology 192, № 1_Supplement (1 травня 2014): 68.3. http://dx.doi.org/10.4049/jimmunol.192.supp.68.3.
Повний текст джерелаАнотація:
Abstract Although accumulating evidence demonstrates that differentiated CD4 cells preserve plasticity to alter phenotypes under various conditions, it is still unclear how stable Th1 cells are and whether Th1 cells can convert into Th17 cells. The high stability of Th1 is supported by some epigenetic studies and numerous reports of Treg and Th17 cells conversion into Th1 cells but not vice versa. However, recent reports of Th1 cell conversion to Treg, Th2 and Tfh cells argue the absolute stability of Th1 lineage. By using IFNγThy1.1 CBir1 TCR transgenic reporter mice, whose TCR is specific for an immunodominant microbiota antigen, we investigate the stability of Th1 cells under intestinal inflammatory conditions. Transfer of purified CBir1 specific IFNγ+Th1 cells induces colitis in RAG-/- mice and IFNγ+Th1 cells convert into IL-17+ Th17 but not Foxp3+ Treg cells in the inflamed intestines. TGFβ, IL-6 and IL-2, but not hypoxia factors, differentially regulate Th1 to Th17 conversion. TGFβ induction of transcriptional factors, Runx1 and RORγt, is crucial for the conversion, in that silencing Runx1 by siRNA inhibits Th1 conversion into Th17 cells. Furthermore, using ChIP assay, we show that TGFβ enhances histone acetylation but inhibits trimethylation of Runx1 and RORγt binding sites on il-17 or rorc gene in Th1 cells. In conclusion, our data demonstrate that Th1 cells convert into Th17 cells under inflammatory conditions in intestines, which is mediated by TGFβ-induction of Runx1.
7
Annunziato, Francesco, and Sergio Romagnani. "Do studies in humans better depict Th17 cells?" Blood 114, no. 11 (September 10, 2009): 2213–19. http://dx.doi.org/10.1182/blood-2009-03-209189.
Повний текст джерелаАнотація:
Abstract CD4+ T helper (Th) lymphocytes represent a heterogeneous population of cells. In addition to type 1 (Th1) and type 2 (Th2) cells, another subset of CD4+ effector Th cells has been discovered and named as Th17, because of its unique ability to produce interleukin (IL)–17. Studies in mice initially suggested that Th17 cells are the pathogenic cells in autoimmune disorders, whereas Th1 cells may behave rather as protective. Subsequent studies in humans demonstrated the plasticity of Th17 cells and their possibility to shift to Th1. The plasticity of Th17 to Th1 cells has recently been confirmed in mice, where it was found that Th17 cells seem to be pathogenic only when they shift to Th1 cells. Studies in humans also showed that Th17 cells are different than in mice because all of them express CD161 and exclusively originate from CD161+ precursors present in umbilical cord blood and newborn thymus. While murine Th17 cells develop in response to IL-6, IL-1, and transforming growth factor (TGF)–β, human Th17 cells originate from these CD161+ precursors in response to IL-1β and IL-23, the need for TGF-β being controversial. Thus, we believe that studies in humans have better depicted human Th17 cells than studies in mice.
8
Paulos, Chrystal, Michelle Nelson, Logan Huff, Sreenath Kundimi, and Morgan Goodyear. "Human CD26hi Th17 cells eradicate large established mesothelioma (P2139)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 170.26. http://dx.doi.org/10.4049/jimmunol.190.supp.170.26.
Повний текст джерелаАнотація:
Abstract Human CD4+ T cells can differentiate into multiple effector subsets, but their role in anti-tumor immunity remains incompletely elucidated. Further, the costimulatory molecules that effectively bolster their antitumor activity are unknown. To uncover the role of CD28 versus ICOS costimulation, we sorted Th1 (CXCR3+), Th2 (CCR4+), or Th17 (CCR6+ or CD26hi) subsets from bulk human CD4+ T cells and stimulated them with CD3/CD28 or CD3/ICOS beads. We found that ICOS costimulation not only augmented human Th17 cells’ function, but also enhanced the function of human Th1 and Th2 cells superior to CD28 costimulation. Moreover, CD26hi Th17 cells were more polyfunctional than the other T cells subsets, as indicated by increased secretion of IL-17, IFN-γ, IL-22 and TNF-α. To determine the therapeutic potential of these subsets, we sorted Th1, Th2 and Th17 cells from human peripheral blood, expanded them with CD3/ICOS beads, and engineered them to recognize mesothelioma. We found that CD26hi Th17 cells mediated superior regression of large human mesothelioma in mice compared to CXCR3+Th1, CCR4+Th2 or CCR6+Th17 cells. The therapeutic effectiveness of CD26hi Th17 cells was associated with enhanced functionality and persistence in vivo. Taken together, these data indicate that the appropriate selection of effector CD4+ T cells is critical for successful tumor eradication. These findings will help guide next generation clinical trials for patients with advanced malignancies.
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Carvalheiro, Tiago, Carlos Rafael-Vidal, Beatriz Malvar-Fernandez, Ana P. Lopes, Jose M. Pego-Reigosa, Timothy R. D. J. Radstake, and Samuel Garcia. "Semaphorin4A-Plexin D1 Axis Induces Th2 and Th17 While Represses Th1 Skewing in an Autocrine Manner." International Journal of Molecular Sciences 21, no. 18 (September 22, 2020): 6965. http://dx.doi.org/10.3390/ijms21186965.
Повний текст джерелаАнотація:
Semaphorin (Sema)4A is a transmembrane glycoprotein that is elevated in several autoimmune diseases such as systemic sclerosis, rheumatoid arthritis and multiple sclerosis. Sema4A has a key role in the regulation of Thelper Th1 and Th2 differentiation and we recently demonstrated that CD4+ T cell activation induces the expression of Sema4A. However, the autocrine role of Sema4A on Th cell differentiation remains unknown. Naïve Th cells from healthy controls were cell sorted and differentiated into Th1, Th2 and Th17 in the presence or absence of a neutralizing antibody against the Sema4A receptor PlexinD1. Gene expression was determined by quantitative PCR and protein expression by ELISA and flow cytometry. We found that the expression of Sema4A is induced during Th1, Th2 and Th17 differentiation. PlexinD1 neutralization induced the differentiation of Th1 cells, while reduced the Th2 and Th17 skewing. These effects were associated with an upregulation of the transcription factor T-bet by Th1 cells, and to downregulation of GATA3 and RORγt in Th2 cells and Th17 cells, respectively. Finally, PlexinD1 neutralization regulates the systemic sclerosis patients serum-induced cytokine production by CD4+ T cells. Therefore, the autocrine Sema4A-PlexinD1 signaling acts as a negative regulator of Th1 skewing but is a key mediator on Th2 and Th17 differentiation, suggesting that dysregulation of this axis might be implicated in the pathogenesis of CD4+ T cell-mediated diseases.
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Clay, Slater L., Alberto Bravo-Blas, Daniel M. Wall, Megan K. L. MacLeod, and Simon W. F. Milling. "Regulatory T cells control the dynamic and site-specific polarization of total CD4 T cells following Salmonella infection." Mucosal Immunology 13, no. 6 (May 26, 2020): 946–57. http://dx.doi.org/10.1038/s41385-020-0299-1.
Повний текст джерелаАнотація:
Abstract FoxP3+ regulatory T cells (Tregs) control inflammation and maintain mucosal homeostasis, but their functions during infection are poorly understood. Th1, Th2, and Th17 cells can be identified by master transcription factors (TFs) T-bet, GATA3, and RORγT; Tregs also express these TFs. While T-bet+ Tregs can selectively suppress Th1 cells, it is unclear whether distinct Treg populations can alter Th bias. To address this, we used Salmonella enterica serotype Typhimurium to induce nonlethal colitis. Following infection, we observed an early colonic Th17 response within total CD4 T cells, followed by a Th1 bias. The early Th17 response, which contains both Salmonella-specific and non-Salmonella-specific cells, parallels an increase in T-bet+ Tregs. Later, Th1 cells and RORγT+ Tregs dominate. This reciprocal dynamic may indicate that Tregs selectively suppress Th cells, shaping the immune response. Treg depletion 1–2 days post-infection shifted the early Th17 response to a Th1 bias; however, Treg depletion 6–7 days post-infection abrogated the Th1 bias. Thus, Tregs are necessary for the early Th17 response, and for a maximal Th1 response later. These data show that Tregs shape the overall tissue CD4 T cell response and highlight the potential for subpopulations of Tregs to be used in targeted therapeutic approaches.
11
Glosson, Nicole, Sarita Sehra, Qing Yu, Gretta Stritesky, Evelyn Nguyen, and Mark Kaplan. "Th17 cells demonstrate stable cytokine production in allergic inflammation (P1143)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 50.14. http://dx.doi.org/10.4049/jimmunol.190.supp.50.14.
Повний текст джерелаАнотація:
Abstract Th17 cells are critical for the clearance of extracellular bacteria and fungi, but also contribute to the pathology of autoimmune diseases and asthma. Th17 cells can acquire a Th1-like phenotype in vitro and in vivo, but less is known about their ability to adopt Th2 and Th9 effector programs. To explore this in more detail, we generated an IL-17F lineage tracer mouse strain that allows tracking of cells that formerly expressed IL-17F and can be used to test stability of the Th17 phenotype. Th17 cells cultured under polarizing conditions that promote Th1, Th2 or Th9 differentiation adopt the respective effector programs, expressing lineage associated transcription factors, and secreting IFN-γ, IL-4 or IL-9, while diminishing IL-17 production and expression of RORγt. To explore the stability of Th17 cells in an in vivo environment that is associated with the development of Th2 and Th9 cells, we used the adjuvant-dependent, OVA/Alum and the adjuvant-free, house dust mite models of allergic airway disease (AAD). In both models of AAD, Th17 cells from the lungs of diseased mice did not secrete alternative cytokines nor adopt Th1, Th2 or Th9 effector programs, but remained stable IL-17-secretors. Thus, although Th1-biased pro-inflammatory environments have been shown to induce alternative cytokine expression from Th17 cells in vivo, our data suggest that during allergic inflammatory disease, Th17 cells are remarkably stable, and retain the potential to produce IL-17.
12
Nishimori, Hisakazu, Yoshinobu Maeda, Takanori Teshima, Haruko Sugiyama, Koichiro Kobayashi, Yoshiko Yamasuji, Sachiyo Kadohisa, et al. "Synthetic retinoid Am80 ameliorates chronic graft-versus-host disease by down-regulating Th1 and Th17." Blood 119, no. 1 (January 5, 2012): 285–95. http://dx.doi.org/10.1182/blood-2011-01-332478.
Повний текст джерелаАнотація:
Abstract Chronic GVHD (cGVHD) is a main cause of late death and morbidity after allogeneic hematopoietic cell transplantation, but its pathogenesis remains unclear. We investigated the roles of Th subsets in cGVHD with the use of a well-defined mouse model of cGVHD. In this model, development of cGVHD was associated with up-regulated Th1, Th2, and Th17 responses. Th1 and Th2 responses were up-regulated early after BM transplantation, followed by a subsequent up-regulation of Th17 cells. Significantly greater numbers of Th17 cells were infiltrated in the lung and liver from allogeneic recipients than those from syngeneic recipients. We then evaluated the roles of Th1 and Th17 in cGVHD with the use of IFN-γ–deficient and IL-17–deficient mice as donors. Infusion of IFN-γ−/− or IL-17−/− T cells attenuated cGVHD in the skin and salivary glands. Am80, a potent synthetic retinoid, regulated both Th1 and Th17 responses as well as TGF-β expression in the skin, resulting in an attenuation of cutaneous cGVHD. These results suggest that Th1 and Th17 contribute to the development of cGVHD and that targeting Th1 and Th17 may therefore represent a promising therapeutic strategy for preventing and treating cGVHD.
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Adair, Patrick, Yongchan Kim, Kathleen Pratt, and David Scott. "Engineered FVIII-specific human CD4 T cells: does TCR avidity modulate T-helper phenotypes? (IRC7P.425)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 128.6. http://dx.doi.org/10.4049/jimmunol.194.supp.128.6.
Повний текст джерелаАнотація:
Abstract We recently demonstrated that expanded human CD4 T cells can be transduced to express TCRs specific for a given epitope. These cells proliferate and secrete cytokines in response to their cognate peptide/MHC. Herein, we examined whether TCR- transduced cells could be skewed to different T-helper subsets, or alternatively if previously skewed T cells could be modulated after transduction. Two HLA DR1-restricted TCRs were cloned from Th2 and Th17/Th1-type CD4+ T-cell clones specific for a coagulation factor VIII peptide (pC2). Engineered CD4+ T cells expressing these TCRs exhibited different proliferation kinetics during titration with pC2. All pC2-stimulated cells expressed IFN-g, IL-4, and IL-2 intracellularly but did not express cytokine signatures characteristic of their parental Th2 and Th17/Th1 clones. CD45RA+ and CD45RA- T cells were skewed to Th1, Th2 or Th17 and then transduced with each of the 2 TCRs. The higher-avidity TCR cells that were skewed to Th2 and then stimulated with low [pC2] maintained a Th2 cytokine signature, whereas the same cells stimulated with higher [pC2] expressed lower levels of IL-4 and GATA3. In contrast, Th1, Th17 and Th0-skewed cells transduced with the same TCR expressed their respective cytokines at all pC2 doses. Differences between the low-avidity TCR-engineered cells were less pronounced. These studies will inform our strategies for designing novel T-helper cellular therapies.
14
Feng, Ting, Hongwei Qin, Lanfang Wang, Etty Benveniste, Charles Elson, and Yingzi Cong. "Microbiota antigen specific Th17 cells induce colitis and promote Th1 cell response through IL-17 induction of innate cell IL-12 and IL-23 production (47.3)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 47.3. http://dx.doi.org/10.4049/jimmunol.184.supp.47.3.
Повний текст джерелаАнотація:
Abstract Both Th1 and Th17 cells have been implicated in the pathogenesis of IBD and experimental colitis. However, the complex relationship between Th1 and Th17 cells has not been completely analyzed. Although it has been shown recently that Th17 cells can convert into Th1 cells, the underlying in vivo mechanisms and the role of Th1 cells converted from Th17 cells in colitis pathogenesis are still largely unknown. By using Thy1.1-IFNγ reporter mice and IL-17 capture technique, we generated Th1 and Th17 cells of high purity from immunodominant microbiota antigen CBir1 flagellin specific TCR transgenic mice. Highly purified Th1 and Th17 cells differentially induced colitis, in that Th1 cells induced mild, whereas Th17 cells induced severe colitis when transferred into TCRβxδ-/- mice. In the colitic Th17 recipients, substantial IFNγ+ Th1 cells emerged in intestinal lamina propria. Colonic tissues of Th17 recipients produced high levels of IL-12 and IL-23. IL-17 treatment induced BMDC IL-12 and IL-23 production in vitro. Administration of anti-IL-17 mAb to Th17 recipients abrogated colitis development, blocked colonic IL-12 and IL-23 production, and inhibited T cell IFNγ production. Furthermore, colon-conditioned medium of colitic Th17 cell recipients promoted IFNγ production by Th17 cells, which was inhibited by the addition of anti-IL-12 and anti-IL-23 mAb. These data indicate that Th17 cells promote Th1 cells through IL-17 induction of mucosal innate cell IL-12 and IL-23 production.
15
Kotake, Shigeru, Yuki Nanke, Toru Yago, Manabu Kawamoto, Tsuyoshi Kobashigawa, and Hisashi Yamanaka. "Elevated Ratio of Th17 Cell-Derived Th1 Cells (CD161+Th1 Cells) to CD161+Th17 Cells in Peripheral Blood of Early-Onset Rheumatoid Arthritis Patients." BioMed Research International 2016 (2016): 1–5. http://dx.doi.org/10.1155/2016/4186027.
Повний текст джерелаАнотація:
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by the destruction of articular cartilage and bone with elevated levels of proinflammatory cytokines. It has been reported that IL-17 and Th17 cells play important roles in the pathogenesis of RA. Recently, plasticity in helper T cells has been demonstrated; Th17 cells can convert to Th1 cells. It remains to be elucidated whether this conversion occurs in the early phase of RA. Here, we tried to identify Th17 cells, Th1 cells, and Th17 cell-derived Th1 cells (CD161+Th1 cells) in the peripheral blood of early-onset RA patients. We also evaluated the effect of methotrexate on the ratio of Th17 cells in early-onset RA patients. The ratio of Th17 cell-derived Th1 cells to CD161+Th17 cells was elevated in the peripheral blood of early-onset RA patients. In addition, MTX reduced the ratio of Th17 cells but not Th1 cells. These findings suggest that IL-17 and Th17 play important roles in the early phase of RA; thus, anti-IL-17 antibodies should be administered to patients with RA in the early phase.
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Horie, Ichiro, Norio Abiru, Yuji Nagayama, Genpei Kuriya, Ohki Saitoh, Tatsuki Ichikawa, Yoichiro Iwakura, and Katsumi Eguchi. "T Helper Type 17 Immune Response Plays an Indispensable Role for Development of Iodine-Induced Autoimmune Thyroiditis in Nonobese Diabetic-H2h4 Mice." Endocrinology 150, no. 11 (September 24, 2009): 5135–42. http://dx.doi.org/10.1210/en.2009-0434.
Повний текст джерелаАнотація:
T helper type 1(Th1)/Th2 paradigm has been expanded by discovery of a novel effector T cell (Teff) subset, Th17 cells, which produce a proinflammatory cytokine IL-17. Th17 cells have recently been shown to play a major role in numerous autoimmune diseases that had previously been thought to be Th1-dominant diseases. We here studied the significance of Th17 cells in iodine-induced autoimmune thyroiditis in nonobese diabetic-H2h4 mice, a mouse model of Hashimoto’s thyroiditis in humans, which spontaneously develop antithyroglobulin autoantibodies and intrathyroidal lymphocyte infiltration when supplied with iodine in the drinking water. We observed increased numbers of Th1 and Th17 cells in spleen and accumulation of both types of Teff in the thyroid glands of iodine-fed wild-type mice, indicating that Th17 cells as well as Th1 cells constitute thyroid lesions. Furthermore, the incidence and severity of intrathyroidal lymphocyte infiltration, and the titers of antithyroglobulin autoantibodies were markedly reduced in iodine-treated IL-17−/− mice as compared with wild-type mice. Of interest, IL-17+/− mice showed an intermediate phenotype. Therefore, the present study, together with a previous report demonstrating the importance of Th1, not Th2, immune response for developing thyroiditis using mice deficient for interferon-γ or IL-4, clearly indicates that both Th1 and Th17 cells are critical Teff subsets for the pathogenesis of spontaneous autoimmune thyroiditis in nonobese diabetic-H2h4 mice.
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MAHENDRA, ANKIT, RAMNATH MISRA, and AMITA AGGARWAL. "Th1 and Th17 Predominance in the Enthesitis-related Arthritis Form of Juvenile Idiopathic Arthritis." Journal of Rheumatology 36, no. 8 (June 16, 2009): 1730–36. http://dx.doi.org/10.3899/jrheum.081179.
Повний текст джерелаАнотація:
Objective.A Th1 biased immune response in synovial fluid has been reported in children with polyarticular and extended oligoarticular-type juvenile idiopathic arthritis (JIA). We investigated T cell phenotypes including Th1, Th2, Th17, and Treg with emphasis on Th17 and Treg, in order to differentiate cytokines in the enthesitis-related arthritis (ERA) form of JIA.Methods.The frequencies of Th1, Th2, Th17, and Treg cells were determined by flow cytometry in peripheral blood (PB) and synovial fluid from patients with ERA and healthy subjects. Levels of interleukin 1ß (IL-1ß), IL-6, IL-21, IL-23, and transforming growth factor ß (TGF-ß), cytokines that influence Th17 lineage cells, were measured in paired plasma and synovial fluid (SF) samples by ELISA. Frequencies are expressed as percentages and cytokine levels as pg/ml.Results.There were no differences in blood samples in the frequency of Th1, Th2, Th17, and Treg cells between patients and controls. In paired samples, the median frequency of CD4+IFN-γ+ (20.49 vs 4.03; p < 0.005) and CD4+IL-17+ (2.27 vs 0.57; p < 0.01) cells was significantly higher in SF compared to PB, respectively; whereas the frequency of CD4+IL-4+ (1.79 vs 2.29; p < 0.04) cells was significantly reduced in the SF compared to PB. There was no difference in the frequency of regulatory T cells. Patients receiving methotrexate had fewer Th2 cells, whereas the Childhood Health Assessment Questionnaire score had a negative association with the frequency of Treg. Median levels of IL-1ß (p < 0.008), IL-6 (p < 0.0001), and IL-17 (p < 0.0001) were higher in SF than in plasma and levels of TGF-ß were lower (p < 0.001). Levels of IL-21 were similar in SF and plasma, whereas IL-23 was undetectable.Conclusion.In patients with ERA, peripheral blood Th1, Th2, Th17, and Treg cells were unchanged, but Th1 and Th17 cells were increased and Th2 cells were reduced in the SF compared to blood. Elevated IL-1ß and IL-6 in SF may be responsible for increased Th17 cells.
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Kannan, Arun, Barbara Butcher, Do-Geun Kim, Yong Lee, Margaret Bynoe, Eric Denkers, and Avery August. "Complex role for Interleukin-2 inducible T-cell kinase in T helper differentiation and effector function in vivo (P1204)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 50.44. http://dx.doi.org/10.4049/jimmunol.190.supp.50.44.
Повний текст джерелаАнотація:
Abstract T helper responses are critical for a productive immune response but an inappropriate response results in inflammatory and autoimmune disorders. The tyrosine kinase ITK has been shown to regulate the development of Th2 responses. Here, we show that ITK regulates Th1/Th17 responses as well. We find that Itk-/- mice are more susceptible to infection by Th1 inducing intracellular pathogen T. gondii, with generation of fewer antigen specific Th1 cells in vivo and fewer effector cells ex vivo upon antigen re-challenge. Transfer of WT CD4+ T cells confers protection against infection in Itk-/- mice. Furthermore, WT but not Itk-/- CD4+ T cells can promote the survival of Rag-/- mice infected by T. gondii. Additionally, the absence of ITK is protective during Th1/Th17 mediated Experimental Autoimmune Encephalomyelitis (EAE) with fewer pathogenic Th1 and Th17 effector cells in the periphery. Furthermore, transfer of Itk-/- CD4+ T cells into Tcra-/- mice results in lower severity of EAE compared to mice that receive WT cells suggesting that Itk-/- CD4+ T cells are intrinsically less pathogenic. Finally, using mice that express an analog sensitive mutant of ITK (ITKas) we show that temporally inhibiting the kinase activity of ITK with a genetically selective small-molecule inhibitor impairs development of Th1, Th2, and Th17 lineages. This work has implications for understanding ITK as a therapeutic target for Th2 mediated inflammatory and Th1/Th17 mediated autoimmune disorders.
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Krebs, Christan F., and Oliver M. Steinmetz. "CD4+T Cell Fate in Glomerulonephritis: A Tale of Th1, Th17, and Novel Treg Subtypes." Mediators of Inflammation 2016 (2016): 1–9. http://dx.doi.org/10.1155/2016/5393894.
Повний текст джерелаАнотація:
Multiple studies have identified CD4+T cells as central players of glomerulonephritis (GN). Cells of the Th1 and Th17 responses cause renal tissue damage, while Tregs mediate protection. Recently, a high degree of plasticity among these T cell lineages was proposed. During inflammation, Th17 cells were shown to have the potential of transdifferentiation into Th1, Th2, or alternatively anti-inflammatory Tr1 cells. Currently available data from studies in GN, however, do not indicate relevant Th17 to Th1 or Th2 conversion, leaving the Th17 cell fate enigmatic. Tregs, on the other hand, were speculated to transdifferentiate into Th17 cells. Again, data from GN do not support this concept. Rather, it seems that previously unrecognized subspecialized effector Treg lineages exist. These include Th1 specific Treg1 as well as Th17 directed Treg17 cells. Furthermore, a bifunctional Treg subpopulation was recently identified in GN, which secrets IL-17 and coexpresses Foxp3 together with the Th17 characteristic transcription factor RORγt. Similarities between these different and highly specialized effector Treg subpopulations with the corresponding T helper effector cell lineages might have resulted in previous misinterpretation as Treg transdifferentiation. In summary, Th17 cells have a relatively stable phenotype during GN, while, in the case of Tregs, currently available data suggest lineage heterogeneity rather than plasticity.
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Leipe, Jan, Fausto Pirronello, Hendrik Schulze-Koops, and Alla Skapenko. "Altered T cell plasticity favours Th17 cells in early arthritis." Rheumatology 59, no. 10 (February 6, 2020): 2754–63. http://dx.doi.org/10.1093/rheumatology/kez660.
Повний текст джерелаАнотація:
Abstract Objectives The predominance of differentiated Th17 cells has been implied as a key driver of autoimmune arthritis, including early RA. Because accumulating evidence suggests that Th cell differentiation is a plastic process, we investigated plasticity and underlying molecular mechanisms to address the shift towards the Th17 phenotype in early RA. Methods A cohort of 61 patients with early, active, untreated RA and 45 age- and sex-matched healthy controls were studied. Viable in vitro- and in vivo-generated Th1, Th2 and Th17 cells were FACS-sorted and transdifferentiated under Th1-, Th2- or Th17-inducing conditions. The cytokine Th profile of the transdifferentiated cells was assessed by flow cytometry. Th cell-associated cytokine and transcription factor gene loci were analysed by chromatin immunoprecipitation assay and their expression by quantitative real-time PCR. Results In vitro-generated Th cells showed substantial plasticity, which was similar between RA and healthy controls, whereas in vivo-derived Th1 and Th2 cells from RA patients demonstrated an enhanced plasticity towards IL-17-expressing phenotypes compared with healthy controls. Further, in vivo-generated Th17 cells from RA patients showed a resistance to transdifferentiate into Th1 or Th2 cells. The serum/glucocorticoid-regulated kinase 1–forkhead box protein O1–IL-23 receptor (SGK1–FOXO1–IL-23R) axis together with increased RORC expression was associated with the predominant Th17 phenotype in early RA. Conclusions Our data indicate that in vivo-originated Th subsets are prone to Th17 cell transdifferentiation in early RA, while Th17 cells are resistant to changes in their phenotype. Together, the data imply that an altered plasticity contributes to the Th17 shift in early RA.
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Harbour, Stacey N., Craig L. Maynard, Carlene L. Zindl, Trenton R. Schoeb, and Casey T. Weaver. "Th17 cells give rise to Th1 cells that are required for the pathogenesis of colitis." Proceedings of the National Academy of Sciences 112, no. 22 (May 18, 2015): 7061–66. http://dx.doi.org/10.1073/pnas.1415675112.
Повний текст джерелаАнотація:
Th17 cells reactive to the enteric microbiota are central to the pathogenesis of certain types of inflammatory bowel disease. However, Th17 cells display substantial developmental plasticity, such that some progeny of Th17 cell precursors retain a predominantly IL-17A+ phenotype, whereas others extinguish IL-17 expression and acquire expression of IFN-γ, giving rise to “Th1-like” cells. It remains unclear what role these subsets play in inflammatory bowel disease. Using a Th17 transfer model of colitis, we found that IFN-γ–deficient Th17 cells retained an IL-17A+ phenotype and were unable to induce colitis in recipients. Development of disease required the transition of a subset of Th17 precursors to Th1-like cells and was contingent on the expression of both Stat4 and T-bet, but not the IL-12 or IFN-γ receptors. Moreover, Th17 cells could provide “help” for the development of pathogenic Th1 cells from naïve precursors. These results indicate that Th17 cells are potent mediators of colitis pathogenesis by dual mechanisms: by directly transitioning to Th1-like cells and by supporting the development of classic Th1 cells.
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Yi, Tangsheng, Ying Chen, Lin Wang, Gong Du, Daniel Huang, Dongchang Zhao, Heather Johnston, et al. "Reciprocal differentiation and tissue-specific pathogenesis of Th1, Th2, and Th17 cells in graft-versus-host disease." Blood 114, no. 14 (October 1, 2009): 3101–12. http://dx.doi.org/10.1182/blood-2009-05-219402.
Повний текст джерелаАнотація:
In acute graft-versus-host disease (GVHD), naive donor CD4+ T cells recognize alloantigens on host antigen-presenting cells and differentiate into T helper (Th) subsets (Th1, Th2, and Th17 cells), but the role of Th subsets in GVHD pathogenesis is incompletely characterized. Here we report that, in an MHC-mismatched model of C57BL/6 donor to BALB/c recipient, WT donor CD4+ T cells predominantly differentiated into Th1 cells and preferentially mediated GVHD tissue damage in gut and liver. However, absence of interferon-γ (IFN-γ) in CD4+ T cells resulted in augmented Th2 and Th17 differentiation and exacerbated tissue damage in lung and skin; absence of both IL-4 and IFN-γ resulted in augmented Th17 differentiation and preferential, although not exclusive, tissue damage in skin; and absence of both IFN-γ and IL-17 led to further augmentation of Th2 differentiation and idiopathic pneumonia. The tissue-specific GVHD mediated by Th1, Th2, and Th17 cells was in part associated with their tissue-specific migration mediated by differential expression of chemokine receptors. Furthermore, lack of tissue expression of the IFN-γ–inducible B7-H1 played a critical role in augmenting the Th2-mediated idiopathic pneumonia. These results indicate donor CD4+ T cells can reciprocally differentiate into Th1, Th2, and Th17 cells that mediate organ-specific GVHD.
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Chatterjee, Shilpak, Pravin Kesarwani, Myroslawa Soloshchenko, Jianing Fu, Chrystal Paulos, Xue-Zhong Yu, and Shikhar Mehrotra. "Increasing Th1 phenotype in Th17 cells improves anti-tumor T cells function (VAC7P.1032)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 143.2. http://dx.doi.org/10.4049/jimmunol.194.supp.143.2.
Повний текст джерелаАнотація:
Abstract Immunotherapy of cancer is a promising approach for successful eradication of large and established tumor. While cytolytic CD8+ T cells have been extensively investigated and used for adoptive cell therapy (ACT), accumulating evidence indicates that CD4+ T helper (Th) cells including Th1 and Th17 subsets are also effective in tumor immunotherapy. Although Th1 cells possess key anti-tumor effector functions as IFNγhi, CD107ahi, T-bethi, Granzyme Bhi, but their poor persistence due to lack of stem-cell like characteristic effect long-term tumor control and reduce their potential in ACT. However, Th17 cells programmed ex vivo in TGFβ exhibit increased stem-cell like features and reduced effector function as compared to Th1 cells, which corelates to their increased persistence but reduced long-term tumor control. Herein we identified the ex vivo programming conditions that combine potent Th1 effector conditions with key stemness feature of Th17 to generate hybrid Th17/Th1 cells that exhibit improved control of murine melanoma (B16-F10) and human melanoma (624-MEL), as compared to Th1 or Th17 cells alone. The hybrid Th1/Th17 cells were less susceptible to activation induced cell death, exhibited increased persistence along with potent effector function, and have potential in future translational studies.
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Kubick, Norwin, Patrick C. Henckell Flournoy, Ana-Maria Enciu, Gina Manda, and Michel-Edwar Mickael. "Drugs Modulating CD4+ T Cells Blood–Brain Barrier Interaction in Alzheimer’s Disease." Pharmaceutics 12, no. 9 (September 16, 2020): 880. http://dx.doi.org/10.3390/pharmaceutics12090880.
Повний текст джерелаАнотація:
The effect of Alzheimer’s disease (AD) medications on CD4+ T cells homing has not been thoroughly investigated. CD4+ T cells could both exacerbate and reduce AD symptoms based on their infiltrating subpopulations. Proinflammatory subpopulations such as Th1 and Th17 constitute a major source of proinflammatory cytokines that reduce endothelial integrity and stimulate astrocytes, resulting in the production of amyloid β. Anti-inflammatory subpopulations such as Th2 and Tregs reduce inflammation and regulate the function of Th1 and Th17. Recently, pathogenic Th17 has been shown to have a superior infiltrating capacity compared to other major CD4+ T cell subpopulations. Alzheimer’s drugs such as donepezil (Aricept), rivastigmine (Exelon), galantamine (Razadyne), and memantine (Namenda) are known to play an important part in regulating the mechanisms of the neurotransmitters. However, little is known about the effect of these drugs on CD4+ T cell subpopulations’ infiltration of the brain during AD. In this review, we focus on understanding the influence of AD drugs on CD4+ T cell subpopulation interactions with the BBB in AD. While current AD therapies improve endothelial integrity and reduce astrocytes activations, they vary according to their influence on various CD4+ T cell subpopulations. Donepezil reduces the numbers of Th1 but not Th2, Rivastigmine inhibits Th1 and Th17 but not Th2, and memantine reduces Th1 but not Treg. However, none of the current AD drugs is specifically designed to target the dysregulated balance in the Th17/Treg axis. Future drug design approaches should specifically consider inhibiting CD4+ Th17 to improve AD prognosis.
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Van Sleen, Y., E. Brouwer, M. G. Huitema, W. Abdulahad, M. Sandovici, A. Boots, and K. Van der Geest. "AB0046 NO EVIDENCE FOR DISTURBED TH1 AND TH17 FREQUENCIES IN GCA AND PMR PATIENTS - A STUDY IN THE GRONINGEN GPS COHORT." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1325.2–1326. http://dx.doi.org/10.1136/annrheumdis-2020-eular.4499.
Повний текст джерелаАнотація:
Background:Giant cell arteritis (GCA) is an aging-associated inflammatory disease of the large-sized arteries. GCA clinically and pathogenically overlaps with polymyalgia rheumatica (PMR), which affects the shoulders and hips. In the inflamed tissues, infiltrated CD4+ T-cells display a disturbed Th cell distribution, that may contribute to the development of the diseases. GCA arteries contain pro-inflammatory T-helper 1 (Th1) and Th17 cells, but almost no Th2 cells or regulatory T-cells. In addition to CD4+ T-cells, macrophages are dominant in GCA and PMR tissue infiltrates. We previously found an altered distribution of monocyte subsets, the precursors of macrophages, in the blood of GCA and PMR patients. Others reported changes in the distribution of Th cells in the blood of treatment-naive GCA and PMR patients as well.Objectives:We sought to replicate previous studies showing a disturbed Th cell distribution in the blood of GCA and PMR patients. Next, we aimed to link the disturbed Th cell distribution to the altered monocyte subset counts.Methods:To assess the capacity of circulating T cells to produce lineage cytokines, PBMCs were cultured for 4 hours in the presence of 50 n g/mL PMA, 1.6 μg/mL calcium ionophore and 10μg/mL BFA. Cells were then intracellularly stained for IFNγ (Th1 cells), IL-17 (Th17 cells) and IL-4 (Th2) by flow cytometry. In addition, monocyte subset counts were determined, based on CD14 and CD16 expression. To obtain absolute counts, proportions determined by flow cytometry were corrected by the total CD4+ T-cell and monocyte counts. Th1, Th17 and monocyte subsets were determined in 21 GCA patients, 19 PMR patients and 19 healthy controls (HC). Th2 cells were determined in 10 GCA patients, 10 PMR patients and 10 HC. All GCA and PMR patients were newly-diagnosed and treatment-naive. HC were age- and sex-matched and without any immunomodulatory medication.Results:Both absolute counts and percentages of peripheral Th1 cells, Th17 cells and Th2 cells did not differ between GCA/PMR patients and HC. The monocytosis in GCA and PMR was mainly attributed to an expansion of the classical monocyte subset. Counts of monocyte subsets were not strongly correlated with counts of either Th1 or Th17 cell counts. In GCA patients, the ESR correlated positively with counts of intermediate monocytes (R= 0.63), but this was not observed in PMR patients.Conclusion:Compared to most previous work, we report similar circulating Th1 and Th17 cell counts in HC, but lower counts in treatment-naive GCA patients then previously reported (Table 1). Furthermore, numbers of Th1 and Th17 cells in peripheral blood showed no relationship with monocyte subsets. As our protocol for defining Th1 and Th17 cells appears to be similar to the other studies, we propose differences in patient selection. Alternatively, Th1 and Th17 skewing should be studied at the site of inflammation, since Th1 and Th17 skewing cytokines are all highly expressed by macrophages at the inflammatory site. This study shows the importance of replicating previous research, as key concepts of disease pathology are derived from data on disturbed Th cell distribution.Table 1.Observed median percentages of circulating Th1 and Th17 cells in GCA patients and age-matched HC. Shown are outcomes from several previous studies as well as the present study. Deng et al, Terrier et al and Saadoun et al found elevated Th1 cell percentages in GCA, whereas Samson et al found them lower. All four previous studies showed elevated Th17 percentages in GCA.Th1%Th17%ReferenceGCAHCGCAHCDeng et al.,Circulation, 201020122.20.4Terrier et al.,Arthritis Rheumatol, 201222122.50.5Saadoun et al.,Arthritis Rheumatol, 201522172.50.6Samson et al.,Arthritis Rheumatol, 201210140.70.3This study11120.60.5Disclosure of Interests:Yannick van Sleen: None declared, Elisabeth Brouwer Consultant of: Roche (consultancy fee 2017 and 2018 paid to the UMCG), Speakers bureau: Roche (2017 and 2018 paid to the UMCG), Minke G. Huitema: None declared, Wayel Abdulahad: None declared, Maria Sandovici: None declared, Annemieke Boots Consultant of: Grünenthal Gmbh until 2017, Kornelis van der Geest Speakers bureau: Roche (2019)
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Bălănescu, Paul, Eugenia Bălănescu, and Anca Bălănescu. "IL-17 and Th17 cells in systemic sclerosis: a comprehensive review." Romanian Journal of Internal Medicine 55, no. 4 (December 1, 2017): 198–204. http://dx.doi.org/10.1515/rjim-2017-0027.
Повний текст джерелаАнотація:
Abstract T cells (especially T helper cells) seem to be strongly associated with systemic sclerosis pathogenesis. Th17-IL-17 axis was proved to be involved in the pathogenesis of multiple autoimmune diseases. By performing a comprehensive research of the literature indexed in PubMed database, the current review summarizes current knowledge related to Th17 and IL-17 in systemic sclerosis. While there is promising data suggesting inhibition of Tregulatory and Th1 signals on one hand and promotion of Th17 and Th2 signals on the other, studies that include prospective and integrated analysis of Tregulatory, Th17, Th1, Th2 (cells and derived cytokines) on the same cohort of Ssc patients are warranted.
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Shriver, Leah, Monica Mann, and Bonnie N. Dittel. "Th17 Cells Alone are not Sufficient to Induce CNS Autoimmunity, but can Synergize with Th1 Cells to Induce EAE (129.24)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S222. http://dx.doi.org/10.4049/jimmunol.178.supp.129.24.
Повний текст джерелаАнотація:
Abstract During a primary immune response, CD4 T cells can polarize into two subsets, Th1 or Th2 depending on the cytokine environment. These subsets have been differentially implicated in the pathogenesis of autoimmune (Th1) or allergic (Th2) disorders. Recently a new lineage of T helper cells has been described, Th17 cells, which produce the cytokine IL-17, and evidence has pointed to these cells as key mediators of autoimmune disorders such as the inflammatory demyelinating disease multiple sclerosis (MS). A novel in vitro skewing paradigm shows that the cytokines IL-6, IL-1, TGF-β, and IL-23 are responsible for the development of this lineage. However, to date, no study has examined whether these cells are solely responsible for induction of CNS autoimmunity. We examined this question using an adoptive transfer model of MS in B10.PL mice termed experimental autoimmune encephalomyelitis (EAE). We found that 1 x 106 MBP-specific Th1 cells induced a monophasic disease course, while the same number of Th17 cells did not induce EAE. These data suggest that Th17 cells alone are not sufficient to initiate EAE disease. The adoptive transfer of 0.125 x 106 Th1 T cells did not result in EAE, but when mixed with 1 x 106 Th17 cells the mice exhibited full blown EAE. In a coculture model of immune cell-neuron interaction that mimics neuronal dysfunction during EAE, we found that Th1 cells induced neuronal dysfunction, while Th17 cells did not. These cumulative data suggest that the two T cell subtypes play differential roles that are synergistic during CNS inflammation and that therapeutic targeting of Th17 cells alone may not prevent pathology in diseases such as MS.
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Poloso, Neil, Chau Vu та David Woodward. "TGFβ down-regulates PGE2 receptor subtype 2 in differentiating naïve human CD4+ T cells, resulting in a lack of expression and function in Th17 cells (P6281)". Journal of Immunology 190, № 1_Supplement (1 травня 2013): 193.10. http://dx.doi.org/10.4049/jimmunol.190.supp.193.10.
Повний текст джерелаАнотація:
Abstract Prostaglandin E2 (PGE2) is an important component in inflammatory diseases. Recently, PGE2 has been recognized as playing a critical role in determining CD4+ T helper cell differentiation and expansion (Th1 and Th17, respectively). In order to better understand the role prostaglandins play in differentiated human T-helper cells we determined the expression of various PG receptors in in vitro differentiated human Th1, Th2, and Th17 cells. Surprisingly, we found that while Th1 and Th2 cells express all four PGE2 receptor subtypes, Th17 cells did not express EP2 subtype as determined by qPCR. Stimulation with specific EP receptor agonists confirmed that Th17 cells did not express a functional EP2 receptor. This is in contrast with mouse Th17 which do not show this phenotype. We further found that this down-regulation of EP2 in human Th17 cells was dependent on exposure to TGFβ, and was dose dependent. This is in contrast to TGFβ reported effects on other cell types and also in mouse CD4+ T cells. This finding could explain why differentiated Th17 cells expand in the presence of PGE2, as they down-regulate an important regulatory feedback loop through EP2. Additionally, our data suggests that PGE2 receptor expression and biology in T cells may not translate from rodents to humans.
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Liu, Houpu, Suxia Yao, Yingzi Cong, and Charles Elson. "Commensal flagellated A4 bacteria promote intestinal Th1/Th17 cell development but inhibit Th2 responses (49.3)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 49.3. http://dx.doi.org/10.4049/jimmunol.188.supp.49.3.
Повний текст джерелаАнотація:
Abstract Host and microbiota interact interdependently to maintain intestinal immune homeostasis. As Th1, Th17, and Tregs are present in lamina propria (LP) in the steady condition, mucosal Th2 cells are hardly detected. Some specific commensal organisms have defined effects on mucosal immune functions, e.g., SFB promotes intestinal Th17 whereas B. fragilis and certain Clostridium spp induce Tregs. However, it is still unclear if there are specific commensal organisms downregulating Th2 responses to microbiota. A4 bacteria, a commensal isolated from mouse cecum, produce CBir1 flagellin, a dominant antigen in Crohn’s disease patients and in experimental colitis. In CBir1 TCR transgenic mice, Th1, Th17 and Treg but no Th2 cells are present in intestinal LP. Upon transferred into TCRβxδ-/- mice, CBir1 Tg T cells differentiated into IFN-γ+, IL-17+, FoxP3+ cells but not IL-4+ cells in LP. When stimulated with CBir1 flagellin in vitro, CBir1 Tg CD4+ T cells were able to differentiate into Th1, Th17 and Tregs but resisted Th2 differentiation. Pretreatment of APC with A4 bacterial lysates or CBir1 flagellin, but not with control E. coli, promoted IFN-γ but inhibited IL-4 production of OTII T cells stimulated with OVA and of wild-type T cells stimulated with anti-CD3 under neutral or Th2 polarizing conditions. Collectively, our data reveal that A4 bacteria inhibit Th2 and favor Th1/Th17 responses in intestinal mucosa via production of flagellin, probably through stimulating IFN-γ production.
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Shi, Guangpu, Madhu Ramaswamy, Barbara P. Vistica, Cuiyan Tan, Eric F. Wawrousek, Richard M. Siegel, and Igal Gery. "Th17 cells mediate sustained autoimmune inflammation and are highly resistant to restimulation-induced cell death (137.17)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 137.17. http://dx.doi.org/10.4049/jimmunol.182.supp.137.17.
Повний текст джерелаАнотація:
Abstract Both Th1 and Th17 T-cell subsets can mediate inflammation, but the kinetics of the pathogenic process mediated by these two subsets has not been investigated. Using an experimental system in which TCR-transgenic Th1 or Th17 cells specific for hen egg lysozyme (HEL) induce ocular inflammation in recipient mice expressing eye-restricted HEL, we found important differences in the in vivo behavior of these two subsets. Th1 cells initially proliferated considerably faster and invaded the eye more quickly than their Th17 counterparts, but then disappeared rapidly. By contrast, Th17 cells accumulated and remained the majority of the infiltrating CD4 cells in the eye for at least 15 days after transfer, mediating more long-lasting pathological changes. Th17 cells were highly resistant to restimulation-induced apoptosis, a major pathway by which autoimmune and chronically restimulated Th1 cells are eliminated. Th17 cells had reduced FasL production and resistance to Fas-induced apoptosis relative to Th1 cells despite normal surface expression of Fas. Moreover, Th1 recipient eyes had a higher expression level of FasL than Th17 recipient eyes. Resistance to programmed cell death in Th17 cells may enable more long-lasting responses against pathogens, but may also enable the chronic autoimmune tissue destruction that has been ascribed to Th17 cells.
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Yeh, Wen-I., and Laurie E. Harrington. "Regulation of effector CD4+ T cell functions by Tbet (48.13)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 48.13. http://dx.doi.org/10.4049/jimmunol.182.supp.48.13.
Повний текст джерелаАнотація:
Abstract Many chronic inflammatory diseases, including inflammatory bowel disease and multiple sclerosis, are reported as Th1 mediated disorders; however, recent data from animal models suggests that Th17 cells are responsible for disease. Interestingly, IFNγ does not appear necessary for disease induction, but the key Th1-associated transcription factor Tbet is required. Therefore, we investigated the relationship between Tbet expression and effector CD4 T cell functions. Colitis induced by adoptive transfer of IFNγ KO CD4 T cells resulted in rapid disease and surprisingly over 60% of CD4 T cells expressed Tbet. We next examined the kinetics and functions of Tbet in vitro during Th1 and Th17 polarization. Tbet was upregulated within 24 hrs of stimulation under Th1 conditions, but remained low in Th17 cells. Moreover, Th17 differentiation was unaffected by Tbet deficiency. In order to define molecules regulated by Tbet, we examined gene expression in WT and Tbet KO CD4 T cells by microarray analysis. Consistent with our earlier results, Th1 associated cytokines were reduced but Th17 and Th2 associated genes were elevated in Tbet KO CD4 T cells. Notably, both the mRNA and protein levels of IL-10, an inhibitory cytokine, are increased in Tbet KO CD4 T cells suggesting a potential role for IL-10 in vivo. In conclusion, we propose that Tbet is critical in maintaining pathogenic Th1 cells and suppressing IL-10 expression.
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Dhume, Kunal, Caroline M. Finn, and Karl Kai McKinstry. "Highly protective T-h17-polarized responses against Influenza A Virus develop in the absence of CD4 T cell-intrinsic T-bet and Eomes expression." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 65.06. http://dx.doi.org/10.4049/jimmunol.206.supp.65.06.
Повний текст джерелаАнотація:
Abstract Though bulk CD4 T cell responses against influenza A virus (IAV) are characterized as Th1, expression of the transcription factor T-bet (Tbx21), the ‘master regulator’ of Th1 fate, is not required for mice to clear IAV. While the Tbx21−/− CD4 T cells develop some Th17 characteristics in the infected lung, they still retain relatively high Th1 functionality including robust IFNγ production. Here, we show that the transcription factor Eomesodermin (Eomes) is required for the residual Th1 identity of Tbx21−/− cells by comparing Tbx21−/− and double Tbx21−/−Eomes− /− CD4 T cells in an adoptive transfer model of IAV infection. The Tbx21−/−Eomes−/− cells not only lose Th1 attributes but develop much stronger Th17 attributes versus Tbx21−/− cells. The elaboration of Th17 responses by Tbx21−/− Eomes−/− cells is not a default effector state but requires receipt of both IL-6 and TGFβ in IAV-infected lungs. Similar Th17 identity in the absence of Th1 attributes are seen analyzing CD4 T cells in Tbx21−/−Eomes−/− mice infected with IAV, and this response correlates with protection as CD4 T cell depletion abrogates viral control. To more stringently test the protective capacity of Th17 responses, we transferred in-vitro Th17 primed WT or Tbx21−/−Eomes−/− effectors to unprimed WT hosts and challenged with lethal IAV. Both populations protected, but while WT Th17 cells gained Th1 characteristics in vivo, Tbx21−/−Eomes−/− cells strengthened their Th17 functionality remarkably without any shift towards Th1 identity. Our observations thus show that prototypical Th17 cells, that cannot gain Th1 attributes through mechanisms of plasticity often seen during pathogen responses, can mediate strong protection against IAV infection.
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Liu, Yingru, та Michael Russell. "Promotion of Th1/Th2 immunity with anti-TGF-β treatment protects mice against Neisseria gonorrhoeae infection and induces immune memory (40.22)". Journal of Immunology 184, № 1_Supplement (1 квітня 2010): 40.22. http://dx.doi.org/10.4049/jimmunol.184.supp.40.22.
Повний текст джерелаАнотація:
Abstract Infection with N. gonorrhoeae triggers an intense inflammatory response characterized by an influx of neutrophils, yet natural infection does not induce effective specific immunity or immune memory. Our previous studies have demonstrated in a murine model of vaginal gonococcal infection that innate immunity governed by Th17 cells was the mainstay of the immune responses elicited by this pathogen. Herein we show in vitro that N. gonorrhoeae could specifically inhibit Th1 and Th2 responses of mouse CD4 T cells, but enhance Th17 response. We found that N. gonorrhoeae increased production of TGF-β by mouse lymphocytes in vitro, and concomitantly suppressed Th1/Th2 cytokines. In mouse vaginal explant cultures, the high constitutive production of TGF-β strengthened the suppressive effect of N. gonorrhoeae on Th1/Th2 responses. Anti-TGF-β, but not anti-IL-17, could divert the immune response to N. gonorrhoeae from Th17 towards Th1/Th2 modes. ELISA, microarray and flow cytometry studies indicated that when mice infected with N. gonorrhoeae were treated with anti-TGF-β, the host Th17 immune response was diminished, while Th1/Th2 responses were enhanced. Anti-TGF-β treatment led to faster clearance of infection and induced protection against secondary challenge, which did not occur in control-treated mice. Our results suggest that N. gonorrhoeae suppresses Th1/Th2-mediated adaptive immune response, and that this effect can be manipulated to enhance specific protective immunity.
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Yu, Yu, Dapeng Wang, Chen Liu, Kane Kaosaard, Kenrick Semple, Claudio Anasetti та Xue-Zhong Yu. "Prevention of GVHD while sparing GVL effect by targeting Th1 and Th17 transcription factor T-bet and RORγt in mice". Blood 118, № 18 (3 листопада 2011): 5011–20. http://dx.doi.org/10.1182/blood-2011-03-340315.
Повний текст джерелаАнотація:
Abstract Allogeneic hematopoietic cell transplantation (HCT) is effective therapy for hematologic malignancies through T cell–mediated GVL effects. However, HCT benefits are frequently offset by the destructive GVHD, which is also induced by donor T cells. Naive Th can differentiate into Th1 and Th17 subsets and both can mediate GVHD after adoptive transfer into an allogeneic host. Here we tested the hypothesis that blockade of Th1 and Th17 differentiation is required to prevent GVHD in mice. T cells with combined targeted disruption of T-bet and RORγt have defective differentiation toward Th1 and Th17 and skewed differentiation toward Th2 and regulatory phenotypes, and caused ameliorated GVHD in a major MHC-mismatched model of HCT. GVL effects mediated by granzyme-positive CD8 T cells were largely preserved despite T-bet and RORγt deficiency. These data indicate that GVHD can be prevented by targeting Th1 and Th17 transcription factors without offsetting GVL activity.
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Lee, Yun Kyung, and Casey T. Weaver. "TCR- independent induction of IL-17 production in TH17 Cells (91.11)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S162. http://dx.doi.org/10.4049/jimmunol.178.supp.91.11.
Повний текст джерелаАнотація:
Abstract Effector CD4 T cells have been classically divided into two lineages, T-helper type 1 (TH1) and TH2. TH1 cells develop in response to intracellular viruses and bacteria and secrete interferon-γ (IFNγ) while TH2 cells produce interleukin (IL)-4 in response to extracellular pathogens. Recent studies have identified a third distinct lineage of effector CD4 T cells called as TH17 that characteristically produce IL-17. The development of TH17 cells depends on TGFβ and IL-6. The published reports establish a direct link between IL-23 and the TH17 cell subset in mediating inflammatory pathology in certain autoimmune diseases although IL-23 is not required for TH17 commitment. We observed that IL-23 acts synergistically with IL-1 or IL-18 to induce IL-17 cytokine production in TH17 cells independent of T cell receptor (TCR) stimulation, analogous to the induction of IFNγ by IL-12 and IL-18 in TH1 cells. Our results suggest that IL-1 or IL-18 signaling might be preceded by IL-23 signaling through the IL-23 receptor (IL-23R), which is upregulated in TH17 by TGFβ. The TH17 effector function is augmented by these non-antigen-specific responses subsequent to their previous antigen-induced differentiation. Our findings help to delineate the role of IL-23 in TH17 cell biology and identify potential targets for prevention of TH17-mediated immunopathology. This work is supported by the National Institutes of Health (C.T.W.).
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Zhang, Qian, Hong Luan, Le Wang, Fan He, Huan Zhou, Xiaoli Xu, Xingai Li, et al. "Galectin-9 ameliorates anti-GBM glomerulonephritis by inhibiting Th1 and Th17 immune responses in mice." American Journal of Physiology-Renal Physiology 306, no. 8 (April 15, 2014): F822—F832. http://dx.doi.org/10.1152/ajprenal.00294.2013.
Повний текст джерелаАнотація:
Antiglomerular basement membrane glomerulonephritis (anti-GBM GN) is a Th1- and Th17-predominant autoimmune disease. Galectin-9 (Gal-9), identified as the ligand of Tim-3, functions in diverse biological processes and leads to the apoptosis of CD4+Tim-3+ T cells. It is still unclear how Gal-9 regulates the functions of Th1 and Th17 cells and prevents renal injury in anti-GBM GN. In this study, Gal-9 was administered to anti-GBM GN mice for 7 days. We found that Gal-9 retarded the increase of Scr, ameliorated renal tubular injury, and reduced the formation of crescents. The infiltration of Th1 and Th17 cells into the spleen and kidneys significantly decreased in Gal-9-treated nephritic mice. The reduced infiltration of Th1 and Th17 cells might be associated with the downregulation of CCL-20, CXCL-9, and CXCL-10 mRNAs in the kidney. In parallel, the blood levels of IFN-γ and IL-17A declined in Gal-9-treated nephritic mice at days 21 and 28. In addition, an enhanced Th2 cell-mediated immune response was observed in the kidneys of nephritic mice after a 7-day injection of Gal-9. In conclusion, the protective role of Gal-9 in anti-GBM GN is associated with the inhibition of Th1 and Th17 cell-mediated immune responses and enhanced Th2 immunity in the kidney.
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Li, Shang, Jing Yu, Chungang Guo, Ying Jie, and Zhiqiang Pan. "The Balance of Th1/Th2 and LAP+Tregs/Th17 Cells Is Crucial for Graft Survival in Allogeneic Corneal Transplantation." Journal of Ophthalmology 2018 (2018): 1–10. http://dx.doi.org/10.1155/2018/5404989.
Повний текст джерелаАнотація:
Purpose. CD4+LAP+ T cells are newly discovered regulatory T cells (Tregs). The aim of this study is to investigate the balance of Th1/Th2 and LAP+Tregs/Th17 in mice after allogeneic corneal transplantation. Methods. A total of 65 mice received orthotopic penetrating transplantation. According to the survival scores of the grafts, the mice were divided into the rejection group and the survival group 3 weeks after transplantation. Th1, Th2, Th17, and regulatory T cells in the ipsilateral drainage lymph nodes and spleens were measured with flow cytometry. The related cytokines in aqueous humor were also analyzed. Results. The frequencies of Foxp3+Tregs, GARP+Tregs, and LAP+Tregs in the survival group were significantly higher than those in the rejection group. And the expression trend of CD4+LAP+ T cells and CD4+GARP+ T cells was consistent. The level of IFN-γ, TNF, IL-6, and IL-17A markedly increased in aqueous humor during corneal allograft rejection. The ratio of Th1/Th2 and Th17/LAP+Tregs significantly increased in the rejection group at the 3rd week after corneal transplantation. Conclusion. LAP+Tregs might be regarded as substitute for Foxp3+Tregs. The balance of Th1/Th2 and LAP+Tregs/Th17 is crucial for corneal allograft survival.
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Zhou, Rong-Fu, Jian Ou-yang, Da-Yu Chang, Jing-Yan Xu, Bing Chen, Yong-Gong Yang, Qi-Guo Zhang, and Xiao-Yan Shao. "Profiles of Th1, Th2, Th17 and Treg Cells in Patients with Chronic Idiopathic Thrombocytopenic Purpura." Blood 112, no. 11 (November 16, 2008): 3404. http://dx.doi.org/10.1182/blood.v112.11.3404.3404.
Повний текст джерелаАнотація:
Abstract Objective: To explore the profiles of Th1,Th2, Th17 and Treg cells in patients with chronic idiopathic thrombocytopenic purpura. Methods: Samples of peripheral blood were collected from 30 chronic ITP patients ( 9 males and 21 females), aged 41, 21 being in active stage, and 9 in remission stage, and 9 healthy persons in control (3 males and 6 females), aged 36. Peripheral blood was cultured, and activated with PMA/ionomycin when Th1, Th2 and Th17 cells were detected. Flow cytometry was used to measure the intracellular cytokines interferon (IFN)-γ, interleukin (IL)-4 and interleukin (IL)-17 so as to identify the Th1 cells (CD3+ CD8− IFN-γ+ IL-4− cells), Th2 cells (CD3+ CD8− IFN-γ − IL-4+ cells) and IL-17 cells (CD3+ CD8− IL-17+ cells); Treg cells were identified to CD4+ CD25+ Foxp3+ cells and uncultured peripheral blood was used to measured the CD4+ CD25+ Foxp3+ cells by flow cytometry. The ratios of Th1/Th2 were calculated. Results: The Th1/Th2 ratio for patients in active stage was 15.04±9.67, significantly higher than those for patients in remission stage (7.17±5.38, P <0.05) and in control (8.47±3.78, P <0.05); the percentage of Treg cells of the patients in active stage was 0.89±0.58%, significantly decreased than those of patients in remission stage (6.41±1.86%, P <0.001) and in control (6.06±0.85%, P <0.001); the percentage of Th17 cells was 1.94±0.77% for patients in active stage, 2.16±0.52% for patients in remission stage and 1.82±0.58% for patients in control, respectively, and there was no statistic significance between them. Conclusion: Chronic ITP is a Th1 predominant disease; decreased number and function of Treg cells might be one of mechanisms that cause immune regulation dysfunction in chronic ITP; Th17 cells might not play a role in the development of chronic ITP.
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Ding, T., B. C. LI, R. Su, X. F. LI, and C. Wang. "POS1006 ABERRANT Th17 CELLS EXPANSION AND RISK FACTORS IN ANKYLOSING SPONDYLITIS PATIENTS COMPLICATED WITH CARDIOVASCULAR EVENTS." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 771.2–771. http://dx.doi.org/10.1136/annrheumdis-2021-eular.3442.
Повний текст джерелаАнотація:
Background:The incidence of Ankylosing Spondylitis (AS) complicated with cardiovascular diseases (CVD) has increased in recent years [1]. However, identification of risk factors indicating the development of CAD in AS patients is lacking. Th17 cells are increasingly recognized to be important in atherogenesis [2]. However, the role of these cells in the pathogenesis of ankylosing spondylitis patients complicated with cardiovascular events remains elusive.Objectives:This study aimed to assess the level of circulating Th17 cells as well as other lymphocyte subsets such as Treg, Th, Ts, and NK cells in AS combined with CVD, and further to evaluate whether elevations in special PBMC subpopulations in AS patients indicate an increased risk of CVD.Methods:Samples were assessed from 141 AS patients hospitalized at the Second Hospital of Shanxi Medical University (60 AS patients combined with CVD and 81 AS patients without CVD) and 100 healthy controls. The absolute numbers of lymphocytes and CD4+ T cells in peripheral blood were determined using Flow Cytometer. The association between PBMC subpopulations and CVD development in AS patients were analyzed using multivariable logistic regression.Results:1. Compared with AS group, AS with CVD group exhibited significant increases in the number of Th17 cells (P=0.001) and Treg cells (P=0.046). The ratio of Th17/Treg was also increased (P=0.085).2. Analogous increases in the absolute number (P<0.001) and frequency (P<0.001) of Th1 cells, as well as the ratio of Th1/Th2 (P<0.001) and Th1/Treg (P=0.004) were also present in AS with CVD patients, compared to those without CVD.3. Compared to HCs, 141 AS patients showed significantly decreased Treg cells (P<0.012) and increased Th17/Treg (P=0.001).4. Logistic regression showed age (odds ratio: 1.09; 95% CI: 1.035-1.137), hypertension (odds ratio: 3.31; 95% CI: 1.152-9.528), diabetes (odds ratio: 8.03; 95% CI: 1.251-51.503), and elevated level of Th1 number (odds ratio: 1.01; 95% CI: 1.003-1.016) and DD (D-dimer) (odds ratio: 1.00; 95% CI: 1.000-1.002) were significantly correlated with the onset of CVD in AS patients.5. Smoke, increased Th17 level, and use of NSAIDS were also positively correlated with the onset of CVD although the P-values did not reach significant.Conclusion:Our data indicates aberrant expansion of Th17 cells in AS with CVD patients. Moreover, age, hypertension, diabetes, and increased level of Th1 in PBMC and DD are single independent risk factors for the presence of CVD in AS. The mechanisms of atherogenesis in AS may associate with the elevations in Th1 and Th17 cells. Imbalance of Th1/Th2 and Th17/Treg may be shared etiologic pathways of AS and CVD, providing attractive targets for the prevention and therapy of CVD development in AS patients.References:[1]Kim JH, Choi IA. Cardiovascular morbidity and mortality in patients with spondyloarthritis: A meta-analysis. Int J Rheum Dis (2020). doi: 10.1111/1756-185x.13970.[2]Saigusa R, Winkels H, Ley K. T cell subsets and functions in atherosclerosis. Nat Rev Cardiol. 2020 Jul;17(7):387-401. doi: 10.1038/s41569-020-0352-5.Figure 1.Compared with AS group, AS with CVD group exhibited significant increases in the number of Th17 cells (P=0.001) and Treg cells (P=0.046). The ratio of Th17/Treg was also increased (P=0.085). The absolute number (P<0.001) and frequency (P<0.001) of Th1 cells, as well as the ratio of Th1/Th2 (P<0.001) and Th1/Treg (P=0.004) were also present in AS with CVD patients.Disclosure of Interests:None declared.
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Blase, Jennifer, Christopher Eickhoff, and Daniel Hoft. "Comparison of the protective roles of Trypanosoma cruzi-specific Th1 and Th17 cells. (MPF6P.746)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 195.15. http://dx.doi.org/10.4049/jimmunol.192.supp.195.15.
Повний текст джерелаАнотація:
Abstract Trypanosoma cruzi is the protozoan etiology of Chagas disease. T. cruzi-specific Th1 cells are known to be important for protective immunity, while the role of T. cruzi-specific Th17 cells has yet to be explored in detail. TCR-transgenic, T. cruzi-specific CD4+ T cells were differentiated in vitro into Th1 or Th17 cells and co-cultured with T. cruzi-infected peritoneal exudate macrophages. Protection was measured as inhibition of intracellular amastigote replication. In vivo, T. cruzi-specific Th1 or Th17 cells were adoptively transferred into Rag-/- mice along with naïve polyclonal CD8+ T cells. Mice were challenged with T. cruzi, persistent immune responses were measured, and protection was assessed by parasitemia and survival. In vitro, both Th1 and Th17 cells led to protection against intracellular T. cruzi growth in macrophages. Th1-mediated protection involved IFN-γ signaling and nitric oxide production by macrophages. In contrast, Th17-mediated protection was dependent on IL-17A but independent of iNOS induction. The role of reactive oxygen species, autophagy, apoptosis, and mechanisms of lysosomal killing are being studied. More importantly, Th17 cells were significantly more protective than Th1 cells in vivo, involving enhanced expansion of pathogen-specific CD8+ T cells. Thus, Th17 cells have both direct and indirect effects for T. cruzi protective immunity. Furthermore, we report the novel finding that Th17 cells provide important helper effects for CD8+ T cells.
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Park, Hye-Soo, Seunga Choi, Yong-Woo Back, Kang-In Lee, Han-Gyu Choi, and Hwa-Jung Kim. "Mycobacterium tuberculosis RpfE-Induced Prostaglandin E2 in Dendritic Cells Induces Th1/Th17 Cell Differentiation." International Journal of Molecular Sciences 22, no. 14 (July 14, 2021): 7535. http://dx.doi.org/10.3390/ijms22147535.
Повний текст джерелаАнотація:
Prostaglandin E2 (PGE2) is an important biological mediator involved in the defense against Mycobacterium tuberculosis (Mtb) infection. Currently, there are no reports on the mycobacterial components that regulate PGE2 production. Previously, we have reported that RpfE-treated dendritic cells (DCs) effectively expanded the Th1 and Th17 cell responses simultaneously; however, the mechanism underlying Th1 and Th17 cell differentiation is unclear. Here, we show that PGE2 produced by RpfE-activated DCs via the MAPK and cyclooxygenase 2 signaling pathways induces Th1 and Th17 cell responses mainly via the EP4 receptor. Furthermore, mice administered intranasally with PGE2 displayed RpfE-induced antigen-specific Th1 and Th17 responses with a significant reduction in bacterial load in the lungs. Furthermore, the addition of optimal PGE2 amount to IL-2-IL-6-IL-23p19-IL-1β was essential for promoting differentiation into Th1/Th17 cells with strong bactericidal activity. These results suggest that RpfE-matured DCs produce PGE2 that induces Th1 and Th17 cell differentiation with potent anti-mycobacterial activity.
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Yu, Xue-Zhong, Cristina Iclozan, Xuexian Yang, Claudio Anasetti, Chen Dong, and Yu Yu. "Resistance of Th17 cells to Activation-Induced Cell Death (47.13)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 47.13. http://dx.doi.org/10.4049/jimmunol.182.supp.47.13.
Повний текст джерелаАнотація:
Abstract Peripheral T cells undergo apoptosis induced by repeated TCR stimulation, known as activation-induced cell death (ACID), which plays an important role in T-cell tolerance. AICD in CD4 T helper (Th) cells including Th1 and Th2 effectors has been extensively studied. Recently, IL-17-producing CD4+ T cells (Th17 cells) have been identified as a unique Th subset, but the susceptibility and underneath molecular mechanism of AICD in Th17 effectors have not been defined. In this study, we found that Th17 cells were significantly less susceptible to AICD upon TCR restimulation compared to Th1 cells. The resistance was confirmed on pure Th17 cells by gating on CD4+RFP+ cells that were polarized from CD4 naïve T cells from il17f/rfp knock-in mice. Furthermore, the resistance of Th17 cells to AICD was also observed when Th17 cells were co-cultured in vitro or co-injected in vivo with Th1 cells. To explore the molecular mechanism, we found that Th17 cells were defective in FasL expression and in caspase activation, but highly expressed anti-apoptotic protein c-FLIP. After knocking down c-FLIP with its specific siRNA, Th17 cells re-expressed FasL and underwent rapid apoptosis upon TCR restimulation. In conclusion, Th17 cells are resistant to AICD likely because the high level of c-FLIP prevents Fas-mediated apoptosis. The resistance of Th17 cells to AICD reveals additional mechanism to explain the high pathogenicity of Th17 cells in autoimmune diseases, and may also provide a rationale to generate tumor-specific Th17 cells for adoptive cell immunotherapy.
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Duhen, Thomas, Chester Ni, and Daniel Campbell. "Identification of a specific gene signature in human Th1/17 cells (BA13P.126)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 177.12. http://dx.doi.org/10.4049/jimmunol.192.supp.177.12.
Повний текст джерелаАнотація:
Abstract T cells that co-express the chemokine receptors CCR6 and CXCR3 and produce IL-17, IFN-γ, GM-CSF and low IL-10, also known as Th1/17 cells, have been proposed to be highly pathogenic in several autoimmune disorders. To better characterize these cells and examine their relationship with Th1 and Th17 cells, we compared the whole transcriptome of the aforementioned T cell subsets by RNAseq directly ex vivo. Using this approach, we identified groups of genes shared either with Th1 or Th17 cells. The Th1 signature included genes such as TBX21, IL12RB2, GZMK, PRF1 and CCL5, whereas the Th17 signature contained well-established Th17-associated genes (i.e. RORC and KLRB1) as well as those not previously associated with Th17 cells (i.e. CTSH and PTPN13). Interestingly, we also found genes specifically expressed by Th1/17 cells, among which are IL4i1, LTK and ABCB1. The latter, also known as MDR1, encodes for a transmembrane transporter playing a major role in the efflux of drugs and endogenous metabolites across the cell membrane. We confirmed its unique expression on Th1/17 cells using a rhodamine efflux assay. Moreover, MDR1+ Th1/17 cells displayed a highly pro-inflammatory cytokine profile. Our data reinforce the notion that Th1/17 cells are a heterogeneous population of cells combining Th1 and Th17 phenotypic and functional characteristics but also that these cells have unique properties that could be targeted as new strategies to combat autoimmune diseases.
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Su, Chuanli, Tao Yang, Zhihong Wu, Jiang Zhong, Yunshu Huang, Tao Huang, and Enjin Zheng. "Differentiation of T-helper cells in distinct phases of atopic dermatitis involves Th1/Th2 and Th17/Treg." European Journal of Inflammation 15, no. 1 (April 2017): 46–52. http://dx.doi.org/10.1177/1721727x17703271.
Повний текст джерелаАнотація:
The aim of this article is to study T-helper (Th) cell differentiation in the progression of acute, subacute, and chronic atopic dermatitis. Skin biopsies from 48 patients with acute, subacute, and chronic atopic dermatitis were studied using immunohistochemistry with antibodies to TARC/CCL17, CTACK/CCL27, and RANTES/CCL5. Peripheral blood mononuclear cells were studied in 17 patients using flow cytometry to measure the content of Th1/Th2 cells and Th17/Treg cells. Levels of interferon (IFN)-γ, interleukin (IL)-4, IL-17A, and transforming growth factor (TGF)-β1 were evaluated with enzyme-linked immunosorbent assay (ELISA). Distinctive expressions of T-cell-specific chemokines TARC/CCL17, CTACK/CCL27, and RANTES/CCL5 were observed at different stages of atopic dermatitis, which were consistent with the differentiation of the Th cell subsets, Th2/Th1, and Th17/Treg. Th2 and Th17 were acute-phase subsets, while Th1 and Treg were chronic-phase subsets. At an early stage of atopic dermatitis, Th17 and Th2 cells were found in peripheral blood mononuclear cells, followed by Th1 cells, Treg cells, and eosinophils; in late-stage or subacute and chronic atopic dermatitis, Th17 and Th2 cell numbers decreased. The levels of the IFN-γ and TGF-β1 increased during the progression of atopic dermatitis from acute to chronic forms. The levels of IL-17A and IL-4 decreased during the progression of atopic dermatitis from acute to chronic forms. The differentiation of Th subsets at distinct phases in atopic dermatitis may form the basis for further studies on the classification or control of this increasingly common clinical condition.
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Hsieh, Tsunghan, Daiki Sasaki, Naoyuki Taira, Hsiaochiao Chien, Shukla Sarkar, and Hiroki Ishikawa. "The AP1 transcription factor JunB is necessary for cell survival of activated CD4+ T cells." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 98.15. http://dx.doi.org/10.4049/jimmunol.206.supp.98.15.
Повний текст джерелаАнотація:
Abstract JunB, an AP-1 transcription factor, interacts with BATF and IRF4 and plays an essential role for differentiation of Th17 cells and effector T regulatory cells. BATF and IRF4 are also important for differentiation of Th1 and Th2 cells, but the role of JunB in those cells is largely unknown. Here we demonstrate that JunB is necessary for survival of Th1 and Th2 cells. JunB is homogenously induced in activated CD4 T cells, and Junb deficiency severely impairs the clonal expansion of those cells in mice immunized with adjuvants that induce Th1, Th2 and Th17 responses. Like BATF and IRF4, JunB promotes cell survival through repressing apoptosis in Th1, Th2 and Th17 cells. However, unlike BATF and IRF4, JunB is not required for regulation of cellular metabolism in those cells. Junb deficiency results in increase of expression of Th1 signature cytokine IFN-γ but does not affect expression of Th2 signature cytokines IL-4 and IL-13 in vivo. Mechanistically, JunB binds to a locus of Bcl2l11 together with BATF and IRF4 and inhibits its product Bim, an apoptosis inducer. Although JunB-mediated chromatin remodeling was observed, it was not linked with the regulation of Bcl2l11, Ifng and Il13. In conclusion, JunB is an essential transcription factor that cooperate with BATF and IRF4 to regulate activated CD4 T cell survival.
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Liang, Ma, Zhang Liwen, Zhuang Yun, Ding Yanbo, and Chen Jianping. "The Imbalance between Foxp3+Tregs and Th1/Th17/Th22 Cells in Patients with Newly Diagnosed Autoimmune Hepatitis." Journal of Immunology Research 2018 (June 27, 2018): 1–12. http://dx.doi.org/10.1155/2018/3753081.
Повний текст джерелаАнотація:
This study is aimed at examining the potential role of regulatory T- (Treg-) Th1-Th17-Th22 cells in the pathogenic process of autoimmune hepatitis (AIH). The numbers of Foxp3+Tregs and Th1, Th17, and Th22 cells were measured in 32 AIH patients using flow cytometry. Moreover, a murine model of experimental autoimmune hepatitis (EAH) was also established and used to investigate the function of Treg-Th1-Th17-Th22 cells in disease progression. AIH patients undergoing an active state had significantly decreased numbers of CD3+CD4+CD25+Foxp3+Tregs and increased numbers of CD3+CD4+CD25−Foxp3+T, CD3+CD4+IFN-γ+Th1, CD3+CD4+IL-17+Th17, and CD3+CD4+IL-2+Th22 cells as well as higher levels of Th1/Th17/Th22-type cytokines compared to AIH patients in remission and HC. Additionally, the numbers of CD3+CD4+CD25+Foxp3+Tregs were negatively correlated with the numbers of Th1-Th17-Th22 cells. Also, the serum levels of IL-17A and IL-22 were correlated positively with liver injury (ALT/AST), whereas the serum levels of IL-10 were correlated negatively with hypergammaglobulinaemia (IgG, IgM) in AIH patients. Interestingly, the percentages of spleen Tregs, expression of Foxp3 mRNA, and liver IL-10 levels decreased, whereas the percentages of spleen Th1-Th17-Th22 cells, expression of T-bet/AHR/RORγt mRNA, and liver IFN-γ, IL-17, and IL-22 levels increased in the murine model of EAH. Our findings demonstrated that an imbalance between Tregs and Th1-Th17-Th22 cells might contribute to the pathogenic process of AIH.
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Zhang, Lin, Junfeng Zhang, Shaohong Su, and Suyan Luo. "Changes in interleukin-27 levels in patients with acute coronary syndrome and their clinical significance." PeerJ 7 (January 4, 2019): e5652. http://dx.doi.org/10.7717/peerj.5652.
Повний текст джерелаАнотація:
Background This study evaluated changes in interleukin (IL)-27 levels in patients with acute coronary syndrome (ACS) and their influence on Th1, Th2, and Th17 cells. Methods Serum levels of IL-27, IL-4, IL-17, and interferon (IFN)-γ in healthy subjects as well as patients with ACS, including stable angina pectoris (SA), unstable angina pectoris (UA), and acute myocardial infarction (AMI), were determined using an enzyme-linked immunosorbent assay. The proportions of Th1, Th2, and Th17 cells among peripheral blood mononuclear cells (PBMCs), were measured using flow cytometry, after incubation with phorbol myristate acetate (PMA) for 4 h. The proportions of Th1 and Th17 cells among PBMCs in AMI and UA were detected after stimulation with IL-27 or PMA + IL-27 for 4, 8, and 12 h. Results Serum levels of IL-27 in patients with AMI and UA were significantly lower than those in SA and control groups, while serum levels of IL-17 and IFN-γ in AMI and UA groups were dramatically increased compared to those in SA and healthy control groups. However, there were no statistically significant differences in serum IL-4. The proportions of Th1 and Th17 cells among PBMCs were statistically significantly higher in the AMI and UA groups than those in the SA and control groups, while there was no statistically significant difference in the proportion of Th2 cells among different groups. For patients with AMI and UA, the effect of co-stimulation of PBMCs with PMA and IL-27 was not significantly different from that of PMA single stimulation, while PMA + IL-27 co-stimulation lowered the Th17 cell proportion significantly compared to PMA single stimulation. Discussion Compared to SA patients and healthy controls, patients with ACS (AMI + UA) had lower serum levels of IL-27 and higher proportions of PBMC Th1 and Th17 cells, which could be attributed to the inhibitory effects of IL-27 on the proliferation of Th17 cells. These results indicated that IL-27 could be a novel therapeutic target in ACS patients.
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Dhume, Kunal, Caroline Finn, Ayushi Singh, Joanne Tejero, Priyadharshini Devarajan, Susan L. Swain, and Karl Kai McKinstry. "The T-box transcription factors T-bet and Eomes repress protective Th17 CD4 T cell responses against Influenza A Virus." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 94.8. http://dx.doi.org/10.4049/jimmunol.204.supp.94.8.
Повний текст джерелаАнотація:
Abstract Promoting strong CD4 cell immunity is an attractive strategy to generate a universal Influenza A Virus (IAV) vaccine. Though most CD4 cell responses against IAV are classified as Th1, Th17 and cytotoxic CD4 cells (ThCTL) may also contribute to viral clearance. Interestingly, we find the transcription factor T-bet (Tbx21), the ‘master regulator’ of Th1 differentiation, to be dispensable for protective CD4 responses against IAV. Surprisingly, Tbx21−/− cells develop Th17 characteristics but retain Th1 functionality, highlighted by strong IFN-γ production. While the transcription factor Eomesodermin (Eomes) can compensate for loss of T-bet to promote antiviral CD8 responses, its roles in CD4 cells is still unclear. Here we analyze Eomes−/−, Tbx21−/− and Tbx21−/−Eomes−/− CD4 cell responses against IAV using an adoptive transfer model to determine the extent to which Eomes regulates antiviral CD4 functions. Eomes−/− cells mirrored the prototypical Th1 responses of WT CD4 cells. Strikingly, Tbx21−/−Eomes−/− cells exhibited near complete loss of both Th1 responses and ThCTL function. In contrast, Tbx21−/− Eomes−/− developed stronger Th17 attributes than Tbx21−/− cells. We assessed protection provided by transfer of in vitro Th17-primed WT, Eomes−/−, Tbx21−/− and Tbx21−/−Eomes−/− cells to unprimed WT mice infected with lethal IAV. While WT and Eomes−/− effectors gained Th1 characteristics in vivo, Tbx21−/−Eomes−/− cells strengthened their Th17 phenotype. Remarkably, all of the Th17 effectors were equally protective. Our observations reinforce the concept that Th17 cells can provide strong protection against IAV, independently of Th1 and ThCTL responses, and suggest Th17 cells use unique pathways to do so.
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Ye, Jing, Yuan Wang, Zhen Wang, Qingwei Ji, Ying Huang, Tao Zeng, Haiying Hu, Di Ye, Jun Wan, and Yingzhong Lin. "Circulating Th1, Th2, Th9, Th17, Th22, and Treg Levels in Aortic Dissection Patients." Mediators of Inflammation 2018 (September 6, 2018): 1–10. http://dx.doi.org/10.1155/2018/5697149.
Повний текст джерелаАнотація:
Background. Previous studies demonstrated that the subsets of CD4+ T helper (Th) cells are closely related to vascular diseases, including atherosclerosis and hypertension. This study is aimed at investigating the circulating Th1, Th2, Th9, Th17, Th22, and Treg levels in aortic dissection (AD) patients. Methods. Blood samples from AD (n=56) and non-AD (NAD, n=24) patients were collected, and the circulating levels of Th1, Th2, Th9, Th17, Th22, and Treg cells and their transcription factors and functional cytokines were measured by flow cytometric analysis, quantitative polymerase chain reaction, and enzyme-linked immunosorbent assays, respectively. In addition, the human aortic vascular smooth muscle cells (HASMCs) were treated with saline, angiotensin II (Ang II), or plasma from AD patients. Results. Compared with the levels in the NAD group, the Th1, Th9, Th17, Th22, and their transcription factor levels were increased and the Th2, Treg, and their transcription factor levels exhibited a decreasing trend in AD patients. In addition, higher IFN-γ, IL-9, IL-17, and IL-22 levels and lower IL-4 and IL-35 levels were observed in AD patients. Simple linear regression analysis and binary logistic regression analysis suggested that Th1/IFN-γ, IL-9, Th17/IL-17, and Th22/IL-22 positively regulated the occurrence of AD, while Th2/IL-4 and Treg/IL-35 negatively regulated the occurrence of AD. Plasma from AD patients further increased Bax mRNA levels but decreased Bcl2 and α-SMA mRNA levels in Ang II-treated HASMCs. Conclusions. Changes in Th1, Th2, Th9, Th17, Th22, and Treg activity are associated with the onset of AD. Different subsets of CD4+ T cells play different roles in the presence of AD.
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Cox, Catherine A., G. Shi, H. Yin, B. P. Vistica, E. F. Wawrousek, C.-C. Chan, and I. Gery. "Polarized TCR-Transgenic Th17 Cells Resemble Th1 Cells in Their Capacity to Adoptively Transfer Ocular Inflammation, but Differ in Other Biological Activities (130.44)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S236. http://dx.doi.org/10.4049/jimmunol.178.supp.130.44.
Повний текст джерелаАнотація:
Abstract The role of Th17 lymphocytes in immunopathogenic processes has been well established, although little is known about their mode of action and other biological activities. Here, we prepared polarized populations of TCR-transgenic (Tg) Th1 or Th17 cells specific against hen egg lysozyme (HEL) and compared each line for its capacity to adoptively transfer ocular inflammation into Tg recipients expressing lens-associated HEL, as well as for other biological activities. To establish each line, naive CD4+ cells were cultured in the presence of HEL and "cocktails" containing cytokines and antibodies known to drive polarization to Th1 or Th17. Successful polarization of Th1 and Th17 lines was confirmed by intracellular expression and release into the culture medium of IFNγ or IL17, respectively. Surface marker expression was determined by flow cytometry of cultured cells. Recipient eyes were examined histologically. Polarized cells were also tested for their capacity to induce splenomegaly in recipient mice (Chen et al JI 2006). Our results showed that Th1 and Th17 cells were similarly immunopathogenic, transferring ocular inflammation at doses as low as 0.2 million. Histological comparison of eyes from each group, however, revealed slight although discernible differences between Th1 and Th17 recipients. The two populations also differed in their expression of surface markers, particularly in CD49d and CD62L. Finally, Th17 cells were remarkably less efficient than Th1 cells in their capacity to induce splenomegaly in recipient mice.