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Vas, Jaya, Jochen Mattner, Albert Bendelac, Amy Howell, Stewart Richardson, Rachel Ndonye, and Marc Monestier. "Activation of NKT cells exacerbates environmentally induced autoimmunity (130.23)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S232. http://dx.doi.org/10.4049/jimmunol.178.supp.130.23.
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Abstract Administration of subtoxic doses of mercuric chloride to genetically susceptible mice induces an autoimmune syndrome with anti-nucleolar antibody production, polyclonal B cell activation and nephritis. We investigated the role of natural killer T (NKT) cells in the modulation of this autoimmune model. Activation of NKT cells by synthetic variants of α-galactosyl ceramide worsened manifestations of mercury-induced disease. Exposure to heat killed Sphingomonas capsulata which contains NKT cell ligands in its cell wall also worsened disease manifestations. We used this model to further elucidate the interplay between NKT cells and other immune cell types. Mice can be tolerized to mercuric chloride by administration of a very low dose of the chemical. Tolerance establishment requires antigen presentation in the steady state by dendritic cells to elicit CD4+ CD25+ regulatory T cells. Activation of NKT cells by a synthetic ligand was able to completely prevent induction, but was by itself unable to break already established tolerance. Dual stimuli (NKT cell activation and TLR 9 ligation) were required to break established tolerance. This study demonstrates that NKT cell activation worsens chemically- induced autoimmunity and also shows a synergy between NKT and TLR ligands in potentiating disease manifestations. Supported by a NIH grant.
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Webster, Kylie, Konstantinos Kyparissoudis, Dale Godfrey, and Jonathan Sprent. "IL-2/ IL-2 mAb treatment generates prolonged expansion and increased cytokine production by NKT cells (50.42)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 50.42. http://dx.doi.org/10.4049/jimmunol.184.supp.50.42.
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Abstract Regulatory T cells can be dramatically boosted in vivo by stimulation with a complex of IL-2 and an IL-2 mAb (JES6-1). The swift 15-fold expansion creates a tolerogenic environment that significantly perturbs autoimmunity and allograft rejection. We recently observed that IL-2/mAb treatment also expands Natural Killer T (NKT) cells, a glycolipid-specific, CD1d-restricted T cell lineage implicated in both regulatory and immunogenic responses. Interestingly, the phenotype of the IL-2/mAb-expanded NKT cells differed from those expanded with the prototypic NKT ligand, alpha-galactosylceramide (α−GalCer). The IL-2/mAb-expanded NKT cells were relatively stable and contracted slowly. They were hyper-functional, with the capacity to rapidly produce cytokines for several days after stimulation. In comparison, α−GalCer stimulated NKT cells characteristically produce a quick burst of Th1 and Th2 cytokines, an ability that then dramatically declines along with their number in the following days. Interestingly, the range of cytokines produced by IL-2/mAb-NKT cells was broad and included not only IFNγ and IL-4, but also significantly high amounts of IL-10 and IL-13. IL-17, however, was notably reduced. These variations in cytokine production appeared to alter the phenotype of dendritic cells in their vicinity. These data suggest an alternate approach to the expansion of NKT cells, specifically within the context of a regulatory milieu that may be appropriate for tolerance induction.
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Morales-Tirado, Vanessa, Wioleta Luszczek, Marié van der Merwe, and Asha Pillai. "Regulatory Immunotherapy in Bone Marrow Transplantation." Scientific World JOURNAL 11 (2011): 2620–34. http://dx.doi.org/10.1100/2011/768948.
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Every year individuals receive hematopoietic stem cell transplantation (HSCT) to eradicate malignant and nonmalignant disease. The immunobiology of allotransplantation is an area of ongoing discovery, from the recipient's conditioning treatment prior to the transplant to the donor cell populations responsible for engraftment, graft-versus-host disease, and graft-versus-tumor effect. In this review, we focus on donor-type immunoregulatory T cells, namely, natural killer T cells (NKT) and regulatory T cells (Treg), and their current and potential roles in tolerance induction after allogeneic HSCT.
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peng, wang zhan, liu hongyu, li zhuonan, Jorge D. Reyes, James D. Perkins, and li wei. "NKT cells in the liver are important for periferal tolerance induction." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 140.44. http://dx.doi.org/10.4049/jimmunol.196.supp.140.44.
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Abstract NKT cells are mainly located in the liver in mice. The role of liver inherent NKT cells are still unclear. Method In this study, we employed mouse orthotopic liver transplantation and heterotopic heart transplantation models to critical examine the role of liver NKT cells in liver and peripheral tolerance induction. Results NKT cells were increased in the tolerated liver grafts which expressed higher levels of CD95L and PD-L1, while the CD4+CD25+Foxp3+ regulatory T cells (Treg) were markedly increased in the both liver and spleen at day 7 post transplantation. The heart allograft survival were prolonged significantly in the recipient which accepted donor spleen cells by portal vein (p.v.) injection in contract to the recipient which received the donor spleen cells by tail vein (i.v.) injection. In vitro immunological assay revealed that the number of NKT cells in the liver was increased and Treg were increased in both liver and spleen from the p.v. treated mice significantly. The IL-2 expression was decreased, IL-4 and IL-10 were increased. Further, significantly increased IL-4, IL-10, and IFN-γ production was detected from liver NPCs under aGalCer stimulation. Conclusion NKT cells are important to liver transplant tolerance induction, appear to play a key role in down regulation of peripheral immune responses and facilitate CD4+CD25+Foxp3+ Treg induction.
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Li, Wei, Katie Carper, Weigang Wang, Zihui Meng, Jorge D. Reyes, and James D. Perkins. "Manipulating The Liver to Induce Systemic Tolerance to Heart Allografts Through CD4+CD25+ Regulatory T cells and NKT Cells (141.39)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 141.39. http://dx.doi.org/10.4049/jimmunol.182.supp.141.39.
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Abstract The liver has been demonstrated in many models to favor the induction of peripheral tolerance. The mechanisms mediating this phenomenon remain undefined. In this study, we delivered the C3H spleen cells (SCs) into the B6 liver through the portal vein (p.v.) in contrast to tail vein (i.v.) injection to characterize the liver leukocytes by flow cytometry and their function by MLR, ELISPOT, and immunohistochemistry assays. Heterotopic heart transplantation was performed from C3H donors to B6 recipients at day 7 post-treatment. The TCRαβ +NK1.1+ cells (NKT) were significantly increased in the liver, and CD4+CD25+Foxp3+ regulatory T cells (Treg) were markedly increased in the both liver and spleen after p.v. but not i.v. injection of C3H SCs. The proliferative activity of T cells from the p.v. treated mice was significantly suppressed and IL-2 was decreased, IL-4 and IL-10 were increased in vitro, suggesting that the role of the Treg may contribute to these responses. Further, significantly increased IL-4, IL-10, and IFN-γ production was detected from liver nonparenchymal cells under αGalCer stimulation, suggesting the role of liver NKT cells. Heart allograft survival was significantly prolonged in the C3H SCs p.v. treated recipients than in the i.v. treated recipients. Therefore, the liver can serve as a site of systemic tolerance induction. Both NKT cells and CD4+CD25+Foxp3+ Treg appear to be involved in the regulation of peripheral immune responses after antigen immunization of the liver.
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Karakawa, Shuhei, Kazuhiro Nakamura, Keiichi Hara, Yoko Mizoguchi, Mizuka Miki, Hiroshi Kawaguchi, Takashi Sato, Shin-ichiro Nishimura, and Masao Kobayashi. "Reconstitution of Regulatory T Cells Involves in the Development of Acute Graft-Versus-Host Disease after Hematopoietic Stem Cell Transplantation." Blood 112, no. 11 (November 16, 2008): 2204. http://dx.doi.org/10.1182/blood.v112.11.2204.2204.
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Abstract Graft-versus-host disease (GVHD) is a significant complication in hematopoietic stem cell transplantation (SCT). On the other hand, graft-versus-tumor (GVT) effect has been known to be concerned with the prevention of relapses in various hematological or non-hematological malignant disorders. The regulation of GVHD without suppressing GVT effect is a pivotal role in the success of hematopoietic SCT. Recently CD4+CD25+regulatory T cells have been recognized to regulate the maintenance of self-tolerance, and associate with several autoimmune diseases. In transplant immunity, CD4+CD25+regulatory T cells have been reported to regulate GVHD without suppressing GVT effect in several animal studies. Natural killer T (NKT) like cells also have been recognized to associated with the maintenance of self-tolerance by inducing CD4+CD25+regulatory T cells through the production of IL-2. In this study, we examined the roles of CD4+CD25+regulatory T cells and NKT like cells in cases underwent hematopoietic SCT. Blood samples from patients underwent SCT in our institution during past 3 years (7 months through 26 years of age, n =19) were obtained every two weeks until day 90 after SCT. Primary disorders of patients were non-malignant hematological disease such as aplastic anemia (n=3), chronic granulomatous disease (n=8) and malignant disease such as leukemia (n=5), and solid tumors (n=3). Pre-conditioning regimens used in this study were myeloablative regimens in 10 cases and reduced intensity regimens in 9 cases, respectively. The frequencies of CD4+CD25+regulatory T cells were assessed by the expression of CD4 and CD25, and those of NKT like cells were assessed by the expression of CD3, CD16, and CD56 using flow cytometry. The mRNA expression of FOXP3 in purified CD4+CD25+regulatory T cells were determined by quantitative real-time PCR method. In 13 patients who had none or Grade 1 acute GVHD, the frequency of CD4+CD25+regulatory T cells in CD4+ T cells was increased up to 25–90% at early period after SCT and normalized below 20% after day 45 post SCT. On the other hand, four of 6 patients who had acute GVHD (more than Grade 2) showed that the frequency of CD4+CD25+regulatory T cells in CD4+ T cells persisted below 20%. In other one patient, the development of acute GVHD (Grade 2) was associated with decreasing the frequency of CD4+CD25+regulatory T cells (30 to 10%) and the recovery of GVHD was found with increasing CD4+CD25+regulatory T cells (10 to 30%). The mean frequency of CD4+CD25+regulatory T cells in CD4+ T cells on day 15 after SCT was 44% in patients without GVHD and 21% in patients with GVHD (p=0.07). No difference in the expressions of FOXP3 mRNA in purified CD4+CD25+regulatory T cells was noted between patients with GVHD and those without GVHD. The reconstitution pattern of CD3+CD16+CD56+ NKT like cells after SCT was not associated with the development of GVHD. These results suggest that the development of acute GVHD may be strongly associated with the reconstitution of donor derived CD4+CD25+regulatory T cells in CD4+ T cells. The measurement of CD4+CD25+regulatory T cells in CD4+ T cells might lead to the early diagnosis and the prevention of acute GVHD. (Future studies will be needed to examine the association between the frequency of regulatory T cells and GVT effect.)
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Li, Wei, Malcom Duthie, Weigang Wang, Katie Carper, Stuart Kahn, Yvette Latchman, Jorge Reyes, and James Perkins. "The role of liver NKT cells in the regulation of peripheral immune responses (42.9)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S35. http://dx.doi.org/10.4049/jimmunol.178.supp.42.9.
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Abstract We have previously shown that the liver plays an important role in oral tolerance induction. The liver can transfer tolerance to OVA from OVA fed mice to naïve mice. In this study we employed an oral tolerance model by OVA feeding to further explore the mechanisms underlying the role of the liver in oral tolerance induction. OVA feeding, either high dose or low dose, expanded NKT cells in the liver which expressed higher levels of CD95L and PD-L1, a moderate level of PD-1 on the surface, peaked at the 2nd dose feeding in the high dose group and at the 3rd dose feeding in the low dose group. The Foxp3+CD4+CD25+ T regulatory cells (Treg) showed a slight increase in the livers and spleens in the low-fed group, but increased only in the livers in the high-fed group. OVA feeding inhibited NKT cell linked T cell proliferation in both low and high dose fed livers and spleens. Elispot assay revealed an increase in IL-4 and IFN-γ production in the low-fed mice, but increased IL-10 in the high-fed mice. Moreover, the DTH responses to OVA stimulation were increased markedly in the NKT−/− mice with high dose feeding, but showed no significant change in the PD-L1−/− mice compared to that in WT mice. Our results indicate that the liver NKT cells are important in OVA-induced oral tolerance, particularly in high dose feeding. The function of NKT cell appears to depend on CD95L and CD4+CD25+Treg, but not on the PD-1/PD-L1 pathway. IL-10 appears dominant in high dose feeding, while IL-4 and IFN-γ show importance in low dose feeding.
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Kumar, Sanjay, James A. Stokes, Karyn Scissum Gunn, Udai P. Singh, Upender Manne, Selvarangan Ponnazhagan, and Manoj K. Mishra. "Regulatory T cells modulate tumor progression and clearance." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 211.2. http://dx.doi.org/10.4049/jimmunol.196.supp.211.2.
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Abstract Regulatory T (Treg) cells, a distinct lineage of T cells, are required to maintain immunological tolerance. However, the molecular mechanism(s) by which Treg cells modulate tumor growth and clearance needs further investigation. Thus, the goal of this study is to analyze the absolute number and role of Treg cells during tumorigenesis. To achieve this goal, tumor induction studies were performed on C57/B6 mice using transgenic adenocarcinoma mouse prostate (TRAMP) cell lines C1, C2 and C3. Interestingly, TRAMP C1 and C2 are tumorigenic while TRAMP C3 fail to form tumor. C57/B6 mice treated with different tumorigenic concentrations of TRAMP (C1, C2, and C3) cells. The experimental design also included appropriate controls. Developing tumors, spleen and draining lymph nodes were dissected out and single cell suspensions were prepared. Cells were stained with the specific antibodies such as NK cells, NKT cells, CD4, CD8, macrophages, B cells and Treg cells and analyzed using a 13-color flowcytometer. Preliminary data revealed that development of tumors by TRAMP C1 and TRAMP C2 cells and non-tumorigenesis by TRAMP C3 cells was dependent on number of Treg cells in tumor microenvironment. Therefore, the data suggest that the number of Treg cells present in tumor microenvironment may have a direct impact on tumor progression and clearance. Thus, modulating the number of Treg cells in tumor microenvironment may be a successful therapeutic strategy to control tumor progression
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Yao, Zhenyu, Jennifer Clare Jones, Yinping Liu, and Samuel Strober. "Differences in Bcl-2 Expression by T Cell Subsets Alter Their Balance After In Vivo Irradiation to Favor Regulatory NKT Cells and CD4+ CD25+ T Cells in Wild Type But Not p53-/- Mice (141.19)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 141.19. http://dx.doi.org/10.4049/jimmunol.182.supp.141.19.
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Abstract A more nuanced analysis of the changes in the balance of immune cell subsets is needed to understand the impact of radiation on immune function. We show the balance of T cell subsets changes after increasing single doses of total body irradiation(TBI) or after fractionated irradiation of the lymphoid tissues(TLI) of mice. These changes are due to differences in radioresistance and Bcl-2 expression of the NKT, CD4+CD25+ Treg and conventional T cell subsets to favor CD4+Bcl-2hi NKT and CD4+CD25+Bcl-2hi Treg cells. Reduction of the Bcl-2lo mature T cell subsets was at least 100 fold greater than that of the Bcl-2hi subsets. CD4+ NKT cells upregulated Bcl-2 and developed a Th2 bias after irradiation, while conventional T cells failed to do so. GVHD was more severe after bone marrow transplantation in NKT cell deficient than in wild type hosts and the residual NKT cells were 10 fold more abundant in the wild type spleen after the TLI versus TBI. Although the changes in the balance of T cell subsets and increase in Bcl-2hi cells occurred in irradiated wild type mice, these changes did not occur in p53-/- mice. In conclusion, differences in the level of Bcl-2 and associated differences in resistance of T cell subsets to radiation induced p53 dependent apoptosis results in a marked alteration in the balance of T cell subsets favoring NKT cells and CD4+CD25+ T cells that promote transplantation tolerance.
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Simões, LaVoy, and Dean. "Effects of Regulatory T Cell Depletion on NK Cell Responses against Listeria monocytogenes in Feline Immunodeficiency Virus Infected Cats." Viruses 11, no. 11 (October 24, 2019): 984. http://dx.doi.org/10.3390/v11110984.
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Regulatory T cells (Treg) are key players in the maintenance of peripheral tolerance, preventing autoimmune diseases and restraining chronic inflammatory diseases. Evidence suggests Treg cells and NK cells have important roles in feline immunodeficiency virus (FIV) pathogenesis; however, in vivo studies investigating the interplay between these two cell populations are lacking. We previously described innate immune defects in FIV-infected cats characterized by cytokine deficits and impaired natural killer cell (NK) and NK T cell (NKT) functions. In this study, we investigated whether in vivo Treg depletion by treatment with an anti-feline CD25 monoclonal antibody would improve the innate immune response against subcutaneous challenge with Listeria monocytogenes (Lm). Treg depletion resulted in an increased overall number of cells in Lm-draining lymph nodes and increased proliferation of NK and NKT cells in FIV-infected cats. Treg depletion did not normalize expression of perforin or granzyme A by NK and NKT cells, nor did Treg depletion result in improved clearance of Lm. Thus, despite the quantitative improvements in the NK and NKT cell responses to Lm, there was no functional improvement in the early control of Lm. CD1a+ dendritic cell percentages in the lymph nodes of FIV-infected cats were lower than in specific-pathogen-free control cats and failed to upregulate CD80 even when Treg were depleted. Taken together, Treg depletion failed to improve the innate immune response of FIV-infected cats against Lm and this may be due to dendritic cell dysfunction.
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Marrero, Idania, Huiming Sheng, Igor Maricic, Shaohsuan S. Fanchiang, Sai Zhang, Derek Sant’Angelo, and Vipin Kumar. "Negative feedback control of autoimmunity by a novel population of regulatory unconventional CD8+ T cells." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 57.10. http://dx.doi.org/10.4049/jimmunol.202.supp.57.10.
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Abstract Immune tolerance mediated by regulatory T cells is important in the control of homeostasis. The characterization of regulatory CD8 T cells has been hampered by inability to distinguish them from conventional CD8 T cells. We have identified a novel population of unconventional cytotoxic TCRαβ+CD8+ T cells with regulatory properties, called uTr, in both naïve mice and humans. The uTr cells are innate-like, express the promyelocytic leukemia zinc finger (PLZF) transcription factor and display an activated-memory phenotype (CD122high, CD44high,CD62Llow, CD69+). They are CD8αα+, NK1.1+(CD161+ in human), express NK inhibitory receptors and are dependent upon IL-15/IL-2Rβ signaling. A significant decrease in the frequency of uTr cells in PLZF−/− mice suggests their dependency on PLZF expression. Similarly, a significant reduction of uTr cells in Qa-1b−/− mice indicates that a sizable proportion of them are restricted by Qa-1b MHC molecules. The deep-sequencing, RT-PCR and FACS analysis of sorted hepatic uTr cells indicate a polyclonal TCR repertoire in both mice and humans. Adoptive transfer of sorted hepatic uTr cells but not conventional CD8 T cells protects B6 mice from EAE as well as RAG1−/− mice from T cell-induced colitis. The uTr cells secrete IFNγ, IL-4 and IL-17 but not TGFβ and express perforin and granzyme B and the mechanism(s) of regulation is dependent upon perforin. The uTr cells are distinct from other unconventional T cells, including NKT cells, NKT-dependent innate-like CD8 T and MAIT cells. Collectively, we have identified a novel unconventional regulatory CD8 T cells that are involved in a negative feedback mechanism of regulation of autoimmunity and also have important implications for anti-cancer immunity.
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Faunce, Douglas E., and Joan Stein-Streilein. "NKT Cell-Derived RANTES Recruits APCs and CD8+ T Cells to the Spleen During the Generation of Regulatory T Cells in Tolerance." Journal of Immunology 169, no. 1 (July 1, 2002): 31–38. http://dx.doi.org/10.4049/jimmunol.169.1.31.
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Roelofs-Haarhuis, Karin, Xianzhu Wu, and Ernst Gleichmann. "Oral Tolerance to Nickel Requires CD4+ Invariant NKT Cells for the Infectious Spread of Tolerance and the Induction of Specific Regulatory T Cells." Journal of Immunology 173, no. 2 (July 7, 2004): 1043–50. http://dx.doi.org/10.4049/jimmunol.173.2.1043.
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Blazar, Bruce R., Kelli P. A. MacDonald, and Geoffrey R. Hill. "Immune regulatory cell infusion for graft-versus-host disease prevention and therapy." Blood 131, no. 24 (June 14, 2018): 2651–60. http://dx.doi.org/10.1182/blood-2017-11-785865.
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Abstract Current approaches to prevent and treat graft-versus-host disease (GVHD) after stem cell transplantation rely principally on pharmacological immune suppression. Such approaches are limited by drug toxicity, nonspecific immune suppression, and a requirement for long-term therapy. Our increased understanding of the regulatory cells and molecular pathways involved in limiting pathogenic immune responses opens the opportunity for the use of these cell subsets to prevent and/or GVHD. The theoretical advantages of this approach is permanency of effect, potential for facilitating tissue repair, and induction of tolerance that obviates a need for ongoing drug therapy. To date, a number of potential cell subsets have been identified, including FoxP3+ regulatory T (Treg) and FoxP3negIL-10+ (FoxP3-negative) regulatory T (Tr1), natural killer (NK) and natural killer T (NKT) cells, innate lymphoid cells, and various myeloid suppressor populations of hematopoietic (eg, myeloid derived suppressor cells) and stromal origin (eg, mesenchymal stem cells). Despite initial technical challenges relating to large-scale selection and expansion, these regulatory lineages are now undergoing early phase clinical testing. To date, Treg therapies have shown promising results in preventing clinical GVHD when infused early after transplant. Results from ongoing studies over the next 5 years will delineate the most appropriate cell lineage, source (donor, host, third party), timing, and potential exogenous cytokine support needed to achieve the goal of clinical transplant tolerance.
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Van de Keere, Fabienne, and Susumu Tonegawa. "CD4+ T Cells Prevent Spontaneous Experimental Autoimmune Encephalomyelitis in Anti–Myelin Basic Protein T Cell Receptor Transgenic Mice." Journal of Experimental Medicine 188, no. 10 (November 16, 1998): 1875–82. http://dx.doi.org/10.1084/jem.188.10.1875.
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Autoimmune diseases result from a failure of tolerance. Although many self-reactive T cells are present in animals and humans, their activation appears to be prevented normally by regulatory T cells. In this study, we show that regulatory CD4+ T cells do protect mice against the spontaneous occurrence of experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis. Anti–myelin basic protein (MBP) TCR transgenic mice (T/R+) do not spontaneously develop EAE although many self-reactive T cells are present in their thymi and peripheral lymphoid organs. However, the disease develops in all crosses of T/R+ mice with recombination-activating gene (RAG)-1 knockout mice in which transgenic TCR-expressing cells are the only lymphocytes present (T/R− mice). In this study, crosses of T/R+ mice with mice deficient for B cells, CD8+ T cells, NK1.1 CD4+ T (NKT) cells, γ/δ T cells, or α/β T cells indicated that α/β CD4+ T cells were the only cell population capable of controlling the self-reactive T cells. To confirm the protective role of CD4+ T cells, we performed adoptive transfer experiments. CD4+ T cells purified from thymi or lymph nodes of normal mice prevented the occurrence of spontaneous EAE in T/R− mice. To achieve full protection, the cells had to be transferred before the recipient mice manifested any symptoms of the disease. Transfer of CD4+ T cells after the appearance of symptoms of EAE had no protective effect. These results indicate that at least some CD4+ T cells have a regulatory function that prevent the activation of self-reactive T cells.
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Kim, Hyun Jung, Su Jin Hwang, Byoung Kwon Kim, Kyeong Cheon Jung, and Doo Hyun Chung. "NKT cells play critical roles in the induction of oral tolerance by inducing regulatory T cells producing IL-10 and transforming growth factor beta, and by clonally deleting antigen-specific T cells." Immunology 118, no. 1 (May 2006): 101–11. http://dx.doi.org/10.1111/j.1365-2567.2006.02346.x.
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Strong, Beverly S., Tess Rotzler, Ram Wadhwani, Lucas E. Turner, Emily Midura, and Aimen Shaaban. "Self-Engagement Of An NKT Cell Inhibitory Receptor During Development Alters Receptor Expression and Cellular Function." Blood 122, no. 21 (November 15, 2013): 4480. http://dx.doi.org/10.1182/blood.v122.21.4480.4480.
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Invariant NKT (iNKT) cells have been shown to be pro-inflammatory or anti-inflammatory in many pathologic conditions including infections, cancer, autoimmune diseases and allergy. Additionally, early expansion of iNKT cells correlates with successful engraftment and low incidence of graft-versus host disease suggesting a role for iNKT cells in tolerance to allogeneic transplantation. iNKT cells recognize glycolipids bound to CD1d via their T cell receptor (TCR), but also express the inhibitory receptors for MHC class I ligands (MHC I.) Little is known regarding the importance of iNKT cell self-recognition of MHC I during development and the occurrence of autoimmunity, allergy or tolerance to in utero hematopoietic cellular transplantation (IUHCT). Given the importance of NK cell self-recognition during development, we hypothesized that, like NK cells, self-engagement of MHC I inhibitory receptors during development alters the phenotype and function of self-responsive iNKT cells. Prenatal allogeneic chimeras were established by in utero transplantation of Balb/c fetal liver light density cells at E14 into age-matched C57BL/6 fetal recipients. A kinetic evaluation of iNKT cell receptor expression and function was performed after birth. iNKT cells were evaluated for expression of activating (Ly49D) and inhibitory (Ly49A, F, G) receptors specific for the donor MHC I (H-2d.) The functional response of iNKT cell subsets was measured following in vivo activation with KRN7000, the ligand for iNKT cells. Intracellular cytokine production (IFN-gamma and IL-4) production was assessed in the alloresponsive Ly49A+ iNKT cell subset and compared to naïve controls and B10.D2 (H2d) mice. We found that a negligible fraction of iNKT cells expressed the activating Ly49D receptor in either chimera or controls (<1%.) In chimeric mice, the frequency of iNKT cells expressing Ly49A, F, or G did not change significantly. However, the levels of Ly49A expression were significantly reduced on iNKT cells from all organs tested suggesting developmental recognition of donor class I ligands had occurred. These reduced receptor levels did not appear to be due to sequestration as acid stripping did not alter the phenotype. Lastly, Ly49A+ but not Ly49A- iNKT cells in chimeric mice exhibited significantly increased production of IL-4 in response to TCR stimulation suggesting a shift toward a regulatory phenotype. Consistent with this finding, IFN-gamma levels in chimeras were minimally changed compared to controls. These findings indicate that inhibitory receptor self-engagement during development leads to: 1) alterations in receptor expression; 2) shift toward a tolerogenic phenotype in self-responsive iNKT cell phenotypes; and 3) no change in the receptor expression or function of non-responsive iNKT cell phenotypes. Further studies will directly evaluate the impact of self-recognition of iNKT cells in the pathogenesis of autoimmunity and allergy or tolerance following IUHCT. Disclosures: No relevant conflicts of interest to declare.
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Nazimek, Katarzyna, Philip Askenase, and Krzysztof Bryniarski. "Antibody Light Chains Dictate the Specificity of Contact Hypersensitivity Effector Cell Suppression Mediated by Exosomes." International Journal of Molecular Sciences 19, no. 9 (September 7, 2018): 2656. http://dx.doi.org/10.3390/ijms19092656.
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Antibody light chains (LCs), formerly considered a waste product of immunoglobulin synthesis, are currently recognized as important players in the activation of the immune response. However, very little is known about the possible immune regulatory functions of LCs. Recently, we reported that hapten-specific LCs coat miRNA-150-carrying exosomes produced by CD8+ suppressor T cells downregulating the contact hypersensitivity (CHS) reaction in an antigen-specific manner, in mice tolerized by intravenous administration of a high dose of hapten-coupled syngeneic erythrocytes. Thus, the current studies aimed at investigating the role of hapten-specific LCs in antigen-specific, exosome-mediated suppression of CHS effector cells. Suppressor T cell-derived exosomes from tolerized B-cell-deficient µMT−/−, NKT-cell-deficient Jα18−/−, and immunoglobulin-deficient JH−/− mice were nonsuppressive, unless supplemented with LCs of specificity strictly respective to the hapten used for sensitization and CHS elicitation in mice. Thus, these observations demonstrate that B1-cell-derived LCs, coating exosomes in vivo and in vitro, actually ensure the specificity of CHS suppression. Our research findings substantially expand current understanding of the newly discovered, suppressor T cell-dependent tolerance mechanism by uncovering the function of antigen-specific LCs in exosome-mediated, cell–cell communication. This express great translational potential in designing nanocarriers for specific targeting of desired cells.
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Blazar, Bruce R., Roddy S. O'Connor, Michael C. Milone, Michael L. Dustin, James L. Riley, Benjamin G. Vincent, Jonathan S. Serody, et al. "Role of PD-1/PD-L1 in Acute and Chronic Graft Versus Host Disease." Blood 126, no. 23 (December 3, 2015): SCI—8—SCI—8. http://dx.doi.org/10.1182/blood.v126.23.sci-8.sci-8.
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Abstract Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, play an important role in the maintenance of peripheral tolerance. PD-1 is an inhibitory receptor that attenuates TCR signaling. Its expression is inducible on T-cells, B-cells, NKT-cells, and activated monoytes. Interactions between PD-1 and its ligands deliver inhibitory signals that regulate T-cell activation, tolerance, and immune-mediated tissue damage.A blocking anti-PD-1 mAb given at the time of transplant markedly accelerated acute GVHD lethality in preclinical models via an interferon-gamma dependent mechanism. Both PD-L1 and PD-L2 expression were upregulated in the spleen, liver, colon, and ileum of GVHD mice. PD-L2 expression was limited to hematopoietic cells, but hematopoietic and endothelial cells expressed PD-L1. PD-1/PD-L1, but not PD-1/PD-L2, blockade markedly accelerated GVHD-induced lethality. PD-L1-deficient hosts exhibit rapid mortality associated with increased gut T-cell homing and loss of intestinal epithelial integrity, increased donor T-cell proliferation, activation, Th1 cytokine production, and reduced apoptosis. Bioenergetics profile analysis of proliferating alloreactive donor T-cells demonstrated increased aerobic glycolysis and oxidative phosphorylation, hyperpolarized mitochondrial membrane potential, increased superoxide production, and increased expression of a glucose transporter. During acute GVHD, PD-L1 was up-regulated on donor T-cells. Surprisingly, GVHD-induced lethality was significantly reduced in recipients of donor T cells devoid of PD-L1 and associated with reduced PD-L1-/- donor T-cell infiltration into lymphoid organs and gut, a retention of intestinal epithelial integrity, and a lower production of inflammatory cytokines. During GVHD, PD-L1-/- donor T cells showed increased apoptosis and reduced proliferation, as well as reduced glycolysis, glutaminolysis, and fatty acid metabolism. A role for PD-L1 in glucose-mediated acetyl-CoA production was seen, highlighting the important of glucose as an important carbon source in in alloreactive T cells undergoing clonal expansion. Further data support the hypothesis that the PD-1/PD-L1 pathway regulates T-T interaction. Together our studies indicate that PD-L1 expression that is upregulated on alloreactive donor T cells increases their survival and alters their metabolic pathway utilization in GVHD mice. In contrast to acute GVHD models, we have found that PD-1 pathway blockade can reduce chronic GVHD in a mouse model of multi-organ system disease in which one prominent component is bronchiolitis obliterans. This may occur via effects on T follicular regulatory or germinal center B cells. In summary, we have identified distinct consequences of PD-1/PD-L1 engagement in preclinical acute and chronic GVHD models: PD-1/PD-L1 interactions restrain acute GVHD but increase chronic GVHD. These findings illustrate the important but complex regulatory features of this pathway on a wide array of cell types. Our finding suggests PD-1 pathway modulation may provide unique opportunities for altering immune regulation post-transplant. Disclosures Milone: Novartis: Patents & Royalties, Research Funding. Sharpe:Costim Pharmaceuticals: Patents & Royalties.
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Nishikii, Hidekazu, Kim Byung-Su, Yan Chen, Jeanette Baker, Antonio Pierini, Maite Alvarez, Melissa Mavers, Kristina Maas-Bauer, and Robert S. Negrin. "DR3 Signaling Modulates the Function of Foxp3+ regulatory T Cells and the Severity of Acute Graft and Host Disease." Blood 128, no. 22 (December 2, 2016): 2148. http://dx.doi.org/10.1182/blood.v128.22.2148.2148.
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Abstract Background : CD4+Foxp3+ regulatory T cells (Treg) are a subpopulation of T cells, which regulate the immune system and enhance immune tolerance after transplantation. Donor-derived Treg prevent the development of lethal acute graft versus host disease (GVHD) in murine models of allogeneic hematopoietic cell transplantation (HCT). We recently demonstrated that a single treatment of the agonistic antibody to DR3 (Death receptor 3, aDR3) to donor mice resulted in the expansion/activation of donor derived Treg and prevented acute GVHD (Blood 126:546, 2015), although the precise role of DR3 signaling in GVHD has not been elucidated. In this study, we investigated the efficacy of αDR3 treatment to recipient mice in model of murine GVHD. Methods To analyze the DR3 expression in immune cells with or without TCR stimulation, we comprehensively analyzed the cells with multicolor cytometry using viSNE (visualization of stochastic neighbor embedding algorithm). In transplantation experiments, 5x10e6 T cell depleted bone marrow (from WT C57BL/6 mice, H2kb) and 1x10e6 T cells (C57BL/6-Luciferase mice, H2kb) were injected intravenously into lethally irradiated (8Gy in total) BALB/c recipient mice (H2kd). aDR3 was intraperitonealy injected at different time point after transplantation. The transplanted mice were monitored by clinical GVHD score, weight, bioluminescence imaging (BLI) for donor T cell trafficking, and survival time. To investigate the role of donor or recipient derived Treg in this model, in vivo Treg depletion using B6-Foxp3DTR mice was also performed. Results viSNE analysis demonstrated that DR3 was preferentially expressed on resting-Treg (79%), although a subpopulation of CD4+Foxp3-T cells (59%), CD8+T cells (24%), and NK1.1+TCRb+NKT celsl (42%) also expressed DR3. However, DR3 expressions in CD4+Foxp3-T cells and CD8+T cells were elevated after TCR stimulation in vitro (p<0.01). These data suggested that activation of DR3 signaling would also affect the function of conventional T cell upon activation. In the mixed lymphocyte reaction using allogeneic T cells (from WT C57BL/6 mice) and irradiated splenocytes (from BALB/c mice), the activation of DR3 promoted allogeneic T cell proliferation (p<0.01). In transplantation experiments, aDR3 treatment (day 3 after transplant) to animals with ongoing GVHD failed to expand Treg and further promoted donor T cell activation/proliferation with worse outcomes (p<0.05 in BLI study, p<0.01 in survival). However, the prophylactic treatment of animals with aDR3 (day 0 αDR3 and day 2 allogeneic T cells) resulted in the expansion of recipient derived Treg (H2kd+CD4+Foxp3+ cells, p<0.01) and reduced the severity of GVHD with markedly prolonged survival (p<0.001). These data suggest that the function of DR3 signaling was highly dependent on the activation status of the T cells. This survival benefit could be observed even if Treg were depleted from the donor allogeneic T cells (from diphtheria toxin treated B6-Foxp3DTR mice), suggesting that host derived Treg, rather than donor cells, play a critical role in abrogating GVHD in this model. Conclusion In conclusion, we demonstrated that activation through DR3 signaling not only expands and activates Treg, but also further activates conventional alloreactive T cells and has very different clinical impact depending upon the timing of administration. These data provide important information for future clinical translation using modification of DR3 signaling. Disclosures Negrin: Stanford University: Patents & Royalties.
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Giudice, Valentina, Monia Rocco, Giancarlo Villani, Rosa Rosamilio, Luca Pezzullo, Bianca Serio, Idalucia Ferrara, and Carmine Selleri. "The Role of B Regulatory Cells in the Immunological Escape of Tumor Cells in Hodgkin Lymphoma." Blood 128, no. 22 (December 2, 2016): 1768. http://dx.doi.org/10.1182/blood.v128.22.1768.1768.
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Abstract Hodgkin and Reed-Sternberg (HRS) cells in classical Hodgkin Lymphoma (HL) are surrounded by a rich inflammatory infiltrate which aids in their survival and escape from cytotoxic CD8+ T cells (CTLs) and Natural Killer cells (NKs). Within HL environment, T regulatory cells (Tregs) directly suppress the activity of CTLs and NKs, enhancing the tolerance against HRS cells. B regulatory cells (Bregs) have been shown to support the differentiation of Tregs through IL-10 production; thus, we hypothesized that they could have a role in the pathophysiology of HL. We evaluated 30 classic HL patients (M/F: 18/12; median age, 31 years, range 15-62) and 5 healthy controls (HC) for circulating peripheral blood (PB) Bregs, Tregs, CTLs, NKs, and NKTs. Twenty-four of them were new-diagnosed patients (NwHL) and 6 received a previous diagnosis of HL but were in complete remission (CR) for more than 12 months (PvHL). NwHL patients were divided according to the International Prognostic Score (IPS) and the Ann-Arbor Staging System. All subjects were treated following the ABVD protocol (doxorubicin 25 mg/m2, bleomycin 10 U/m2, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2). Flow cytometry was performed on heparinized PB samples with a 5-color Beckman Coulter Cytomics FC500 flow cytometer. Breg (CD19+CD24+), Treg (CD3+CD4+CD25+), CTL (CD3+CD8+), NK (CD3-CD56+), and NKT (CD3+CD56+) levels were measured simultaneously with the PET/CT evaluations, ie at diagnosis, at the end of the second ABVD administration, at the end of treatment, and at 6 and/or 12 months off-therapy. Moreover, Breg levels were compared to IPS and Ann-Arbor staging groups, and also were correlated to the erythrocyte sedimentation rate (ESR) and to the absolute lymphocyte count (ALC). We found decreased circulating Bregs in NwHL and PvHL patients compared to controls (0.39% vs 0.875% vs 1.813%, respectively, p<0.0001). In addition, we found decreased CTLs in NwHL compared to PvHL and HC (2.815% vs 4.057% vs 5.780%, respectively, p=0.0228). Thus, all HL patients showed lower numbers of Bregs, but there were no differences between patients of different IPS or stage. Besides, lower Breg levels were correlated with higher ESR values (r2=0.3193, p=0.0117), while no correlation was found for ALC (r2=0.0414, p=0.3898). The levels of Tregs, NKs, and NKTs were not significantly different between patients and controls at diagnosis. As a result, the greater reduction of Bregs compared to Tregs in PB caused a larger Bregs/Tregs ratio in NwHL and PvHL patients compared to controls (1.014 and 1.003 vs. 5.975, p=0.0094). Further reduction of circulating Bregs was observed in 58% of NwHL patients at the end of the second ABVD administration for patients experiencing both CR and partial remission (PR) (based on PET/CT scans) and in 80% at the end of treatment (71% CR, 29% PR). Interestingly, post-treatment Breg levels of NwHL were initially lower than that of PvHL patients and controls (NwHL post-treatment 0.4062% vs PvHL 0.8750% vs HC1.813%, p=0.0030) but normalized after 6 months off-therapy (1.444%, p=0.6189). Similar trends were observed for CTLs (NwHL post-treatment 4.615% vs NwHL 6 months off therapy 5.603% vs PvHL4.057% vs HC 5.780%, p=0.7558) and Bregs/Tregs ratio (0.9613 vs 5.975, p=0.0678). These data suggest that the B cell depletion phase during chemotherapy may interrupt the positive feedback between B and T cell compartments and the normalization of Bregs and CTLs after treatment may be linked to the restoration of a normal immune response, supporting by the achievement of CR in all patients. Our preliminary data suggest involvement of Bregs in the escape and survival of HRS cells during active disease. Peripheral blood may mirror disease activity in lymphoid tissues. Thus, the decrease of circulating Bregs may be related to the recruitment of these cells to the tumor site; amplification of the Bregs/Tregs ratio may result in a greater Breg-dependent Treg activation with subsequent inhibition of CTL and NK function. Additionally, the normalization of Bregs and the Bregs/Tregs ratio after chemotherapy could be used to predict disease remission. While larger prospective studies are required to validate these results, we present intriguing evidence of the involvement of Bregs in the pathophysiology of HL. Disclosures No relevant conflicts of interest to declare.
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Malard, Florent, Myriam Labopin, Patrice Chevallier, Thierry Guillaume, Alix Duquesne, Sophie Derenne, Eolia Brissot, et al. "Larger Number of Invariant Natural Killer T-Cells in Allogeneic Peripheral Blood Stem Cell Grafts Is Associated with Improved Graft-Versus-Host Disease-Free, Progression-Free Survival after Allogeneic Stem Cell Transplantation." Blood 126, no. 23 (December 3, 2015): 514. http://dx.doi.org/10.1182/blood.v126.23.514.514.
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Abstract Introduction The therapeutic efficacy of allogeneic stem cell transplantation (allo-SCT) relies mostly on the immune-mediated graft-versus-tumor (GVT) activity of the graft. However the beneficial effect of GVT is counterbalanced by the destruction of the tissues of the recipient by the immune effectors of the donor, termed graft-versus-host disease (GVHD). Despite G-CSF mobilized peripheral blood stem cells (PBSC) being used for more than 20 years, literature investigating the impact of the different graft cell subsets on outcome, remains scarce. Therefore, this study aimed to investigate the impact of a comprehensive set of immune cells contained within PBSC grafts on patients' outcome after allo-SCT, using the composite endpoint of GVHD-free and progression-free survival (GPFS) as primary endpoint. Indeed, some cell subset may lead to a decreased incidence of relapse but at the expense of an increased incidence of GVHD or vice versa. The use of the GPFS composite endpoint would allow to overcome this limitation, identifying cellular subsets that correlate with cure without ongoing morbidity. Patients and methods. 80 consecutive patients who underwent allo-SCT in a single center using G-CSF-mobilized PBSCs between 2010 and 2013 and for whom frozen aliquots of the PBSC grafts were available, were included in this study. Immune cell subset quantification was performed by multi-color flow cytometry. Patients median age was 57 years, 57% of patients had a myeloid malignancy and 43% a lymphoid malignancy. Disease risk index was low or intermediate in 79% of patients and high or very high in 21% of patients. The majority of patients received a reduced-intensity conditioning regimen (81%) and in-vivo T-cell depletion using anti-thymocyte globulin (ATG) (91%). GVHD prophylaxis was cyclosporine alone (34%), or in combination with either mycophenolate mofetil (59%) or methotrexate (7%). 65% of patients received grafts from unrelated donors and 35% from matched related donors. Naïve and memory T cell and B cell subsets, regulatory T cells, invariant natural killer T-cells (iNKT), natural killer cells (NK) and dendritic cell subsets were analyzed. Cell subsets were selected for the purpose of this study based on the absence of a strong correlation with another graft subset (Pearson or Spearman correlation >0.8). P-values were not adjusted for multiple comparisons, but only covariates for which the q value is <0.2 are presented. GPFS was defined as survival without disease progression, grade III-IV acute GVHD or chronic GVHD requiring systemic therapy. Results Median follow-up was 36 months. The median numbers of nucleated cells, CD34+ cells, and total T-cells in the allograft were 102.9, 7.2, and 20.7 x 106/kg, respectively. The numbers of nucleated cells, CD34+ cells, T-cells, B-cells, NK cells, and dendritic cells in the PBSC graft, were not significantly associated with overall survival (OS) and GPFS. Invariant NKT cells were the only cell subset associated with GPFS with univariate p-value <0.01 and q values <0.2. Stratifying the entire group of transplant recipients by median value for iNKT cells (median number 0.011x106/kg) showed better GPFS among patients receiving larger number of iNKT cells, being 49% at 2 years, versus 22% for patients receiving <0.011x106/kg iNKT/Kg (p=0.007) (Figure 1). In multivariate analysis, adjusted for patient age, type of donor, disease risk index, GVHD prophylaxis, conditioning regimen intensity and use of ATG, dose of iNKT cells was the only parameter with a significant impact on GPFS (hazard ratio: 0.45, 95% CI: 0.25-0.80, p=0.007). Transplantation with more than the median number of iNKT cells was also associated with a trend toward an improved progression-free survival (59% versus 39% at 2 years, p=0.12) and a decreased risk of extensive chronic GVHD (5.1% versus 17.5% at 2 years, p=0.07). In contrast, the number of iNKT cells transplanted has no impact on grade II-IV aGVHD (10% versus 15%, p=0.49) or overall survival (60% versus 55%, p=0.51). Conclusion Among patients undergoing allo-SCT and receiving a PBSC graft, a higher number of iNKT, a regulatory cell population implicated in immune tolerance and tumor surveillance, is associated with an improved GPFS. These data may pave the way for prospective and active interventions aiming to manipulate the graft content in order to improve allo-SCT outcome. Figure 1. Influence of invariant NKT cells dose on GPFS Figure 1. Influence of invariant NKT cells dose on GPFS Disclosures Moreau: Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mohty:Janssen: Honoraria; Celgene: Honoraria.
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Saito, Akio, Akihiko Yokohama, Hirotaka Nakahashi, Kohtaro Toyama, Takeki Mitsui, Yoko Hashimoto, Hiromi Koiso, et al. "Innate Immunity in Idiopathic Thrombocytopenic Purpura (ITP)." Blood 112, no. 11 (November 16, 2008): 4907. http://dx.doi.org/10.1182/blood.v112.11.4907.4907.
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Abstract Background: Dendritic cells (DCs), natural killer (NK) cells, and invariant NKT (iNKT) cells play important roles in innate immune systems. These cells have recently been shown to be involved in immunoregulation, and some studies have suggested associations with various kinds of autoimmune disease. Conversely, regulatory T cells (Tregs) that are important for peripheral tolerance and Th17 cells that play a central role in maintenance of chronic inflammation are also associated with the pathogenesis of several autoimmune diseases. Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disease mediated by anti-platelet autoantibodies, but relationships to innate immunity are unclear. In addition, the pathogenesis of ITP associated with Helicobacter pylori remains obscure. In particular, the regulation of immune responses by these cells in patients infected with H. pylori has not been investigated. This study analyzed DCs, NK cells, iNKT cells, Tregs and Th17 cells in patients with ITP. Methods: Subjects comprised 31 patients with ITP and 22 healthy donors. Study protocols were approved by the Institutional Review Board of Gunma University Hospital, and written informed consent was obtained from all subjects. Flow cytometry was used to investigate amounts of circulating plasmacytoid DCs (pDCs) (CD123+ HLA−DR+) and myeloid DCs (mDCs) (CD11c+ HLA−DR+) from whole white blood cells, and NK cells (CD3− CD56+), iNKT cells (Vα24+ Vβ11+), Tregs (CD4+ CD25+ Foxp3+) and Th17 cells (CD4+ IL−17A+) from mononuclear cells. The intracellular interleukin (IL)-17A production in CD4+ T-cells activated by phorbol 12-myristate 13-acetate (PMA) and ionomycin was assessed to detect Th17 cells. Results: Both the percentage and numbers of pDCs were significantly reduced in patients compared to healthy controls (p<0.001), while those of mDCs tended to be lower in patients than in controls, but with no significant differences. NK cell counts tended to be higher in patients than in controls and counts of iNKT cells tended to be lower in patients than in controls, but again no significant differences were demonstrated. Notably, Treg levels were comparable between patients and controls, while Th17 cells were significantly increased in patients compared with controls (p<0.002). In all cases, no significant differences were demonstrated between patients with H. pylori-positive and -negative results. Conclusion: These results suggest that alterations in innate immunity as a reduction of pDCs could be associated with the pathogenesis of ITP. Furthermore, as in some autoimmune diseases that have been considered as Th1 diseases, Th17 cells may play an important role in ITP.
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Azevedo, Rita I., Antonio S. Soares, Eduardo Espada, Nadia Camacho, Carlos V. Martins, Fernanda Lourenco, Clara Juncal, Raul Moreno, Jose A. Carmo, and Joao F. Lacerda. "IL-7 and IL-10 Serum Levels Are Potential Immune Biomarkers for Acute Graft-Versus-Host Disease Following Unrelated Hematopoietic Stem Cell Transplantation." Blood 124, no. 21 (December 6, 2014): 5865. http://dx.doi.org/10.1182/blood.v124.21.5865.5865.
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Abstract Acute GVHD (aGVHD) remains a major cause of morbidity in patients who undergo allogeneic hematopoietic stem cell transplantation (HSCT). Although numerous studies have investigated potential immunologic parameters that could predict for aGVHD, there are no validated immune biomarkers presently used in clinical practice. We are currently performing a prospective analysis of immune reconstitution after allogeneic HSCT in different patient cohorts. The goal of the present study is to detect abnormalities of immune reconstitution associated with an inability to maintain T cell tolerance after allogeneic HSCT and to identify specific immunologic biomarkers predictive of aGVHD. We have thus far accrued 36 unrelated HSCT recipients with a median age of 48 years old (16 females; 20 males). The degree of HLA-matching at the allele level between patients and donors was: 10/10 (n=20), 9/10 (n=15), 8/10 (n=1). Graft source consisted of unmanipulated bone marrow (n=18) or peripheral blood stem cells (n=18). All patients received a reduced-intensity conditioning regimen with fludarabine, melphalan and thymoglobulin (dose dependent on the degree of HLA matching), in association with cyclosporine and mycophenolate mofetil for GVHD prophylaxis. A total of 21 patients (58%) developed grades II-IV aGVHD in the first six months post-transplant. Whole blood and serum samples were collected from HSCT recipients 1, 2, 3 and 6 months post-HSCT. To assess the impact of different immune markers on the occurrence of aGVHD, patients were categorized into 2 groups based on the development or not of grade II-IV aGVHD in the first six months post-HSCT. Our comprehensive 7-colour flow cytometry panel encompasses phenotypic markers for relevant T, B, NK, NKT and dendritic cell subsets, further including intracellular markers for the assessment of proliferation and susceptibility to apoptosis within regulatory (Treg), conventional (Tcon) CD4 T cells and CD8 T cell subsets. Serum concentrations of IL-2, IL-7, IL-10, IL-15, IFN-γ and TNF-α were evaluated with a multiplex cytokine assay. Absolute counts of lymphocytes, total T cells, CD4 Tcon, CD4 Treg and CD8 T cells display similar reconstitution patterns in unrelated HSCT recipients with and without aGVHD. However, we have observed a clear trend for higher levels of γδ T cells, both in terms of frequency and absolute counts, in patients who develop aGVHD, particularly at 1 month post-HSCT (Mann Whitney test, P = 0.0699). Furthermore, we found a significantly higher frequency of proliferating cells, as assessed by Ki67 expression, within the CD4 T cell population in patients who do not develop aGVHD, both at 2 and 3 months (Mann Whitney test, P = 0.0400 and P = 0.0177, respectively) post-HSCT. When dissected into proliferating CD4 Tcon and Treg, the frequency of both Ki67+ Tcon and Ki67+ Treg within the CD4 T cell population is higher in patients who do not develop aGVHD in all time-points analysed, reaching statistical significance at months 2 and 3 for Tcon (Mann Whitney test: P = 0.0280 and P = 0.0051, respectively) and at month 6 for Treg (Mann Whitney test, P = 0.0043). We are also quantifying the serum levels of relevant pro-inflammatory, suppressive and homeostatic cytokines in the two patient groups. We have observed that IL-7 serum levels (pg/ml) in the first 3 months post-transplant are significantly lower in patients who develop aGVHD compared to those who do not (Mann Whitney test: Month 1 P = 0.0051; Month 2 P = 0.0177; Month 3 P = 0.0303), whereas IL-10 levels are significantly higher in aGVHD patients (Mann Whitney test: Month 1 P = 0.0442; Month 2 P = 0.0051; Month 3 P = 0.0480). None of the other cytokines analyzed has revealed significant differences between the two groups of patients, although there seems to be a trend for higher IL-15 serum levels in patients who develop aGVHD, particularly in the first two months post-HSCT. These results indicate that in our patient population sensitive methods for the detection of IL-7 and IL-10 serum levels can identify patients at high risk for grades II-IV aGVHD early post-transplant. The accrual of more patients will clarify whether the levels of γδ T cells post-transplant, as well as the frequency of proliferating CD4 Tcon and Treg populations, can also be used as an early indicator for the development of aGVHD. Disclosures No relevant conflicts of interest to declare.
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Rocamora-Reverte, Lourdes, Franz Leonard Melzer, Reinhard Würzner, and Birgit Weinberger. "The Complex Role of Regulatory T Cells in Immunity and Aging." Frontiers in Immunology 11 (January 27, 2021). http://dx.doi.org/10.3389/fimmu.2020.616949.
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The immune system is a tightly regulated network which allows the development of defense mechanisms against foreign antigens and tolerance toward self-antigens. Regulatory T cells (Treg) contribute to immune homeostasis by maintaining unresponsiveness to self-antigens and suppressing exaggerated immune responses. Dysregulation of any of these processes can lead to serious consequences. Classically, Treg cell functions have been described in CD4+ T cells, but other immune cells also harbour the capacity to modulate immune responses. Regulatory functions have been described for different CD8+ T cell subsets, as well as other T cells such as γδT cells or NKT cells. In this review we describe the diverse populations of Treg cells and their role in different scenarios. Special attention is paid to the aging process, which is characterized by an altered composition of immune cells. Treg cells can contribute to the development of various age-related diseases but they are poorly characterized in aged individuals. The huge diversity of cells that display immune modulatory functions and the lack of universal markers to identify Treg make the expanding field of Treg research complex and challenging. There are still many open questions that need to be answered to solve the enigma of regulatory T cells.
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Rustemeyer, Thomas. "Immunological Mechanisms in Allergic Contact Dermatitis." Current Treatment Options in Allergy, April 4, 2022. http://dx.doi.org/10.1007/s40521-022-00299-1.
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Abstract Purpose of the review The understanding of the cellular and molecular pathogenesis of allergic contact dermatitis (ACD) has increased dramatically. Recent findings Besides CD4+ and CD8+ T cells, other cell types such as innate lymphoid cells, natural killer T cells (NKT), natural killer cells, and T regulatory cells have emerged as crucial key players. New immunological insights have unravelled that the predominant effector cell type determines the clinical pictures. Hence, a better understanding of the involvement of distinct effector cells has shed light on the diversity of ACD reactions and subsequent clinical pictures. Another new perspective has arisen in the elicitation phase. Here, Langerhans cells can play a role in the development of immune tolerance and not, as previously thought, exclusively in the allergen-driven hypersensitivity reaction. B cells also appear to play an important role in triggering ACD by secreting IgM antibodies in response to interleukin (IL)-4 produced by NKT cells, leading to complement activation and chemotaxis of immune cells. Summary Allergic contact dermatitis is a delayed-type hypersensitivity reaction triggered by skin contact with the chemical of interest in individuals previously sensitised to the same or a chemically related substance. The understanding of the cellular and molecular pathogenesis of allergic contact dermatitis has improved considerably. In addition to CD4+ and CD8+ T cells, other cell types such as natural killer T cells (NKT) and regulatory T cells have emerged as important participants. The binding of haptens is the first step in the development of allergic contact dermatitis. Haptens are low molecular weight (mostly <500 Dalton) chemicals that are able to penetrate the stratum corneum of the skin or can enter the body upon systemic administration. Haptens are not immunogenic per se but can be effectively recognised by the immune system after binding to a protein carrier. In the clinically inapparent sensitisation phase, Langerhans cells and dendritic cells initiate an adaptive immune response by capturing and processing antigens and presenting them to naïve T cells in the paracortical regions of the lymph nodes. In the elicitation phase, the clinical manifestations of allergic contact dermatitis are the result of a T cell-mediated inflammatory response that occurs in the skin upon re-exposure to the bite and is mediated by the activation of bite-specific T cells in the skin or other organs.