T-cell vaccination leads to suppression of intrapancreatic Th17 cells through Stat3-mediated RORγt inhibition in autoimmune diabetes

Wang, Min; Yang, Liu; Sheng, Xiaoyan; Chen, Weilei; Tang, Haiqing; Xi, Beili; Zang, Ying

doi:10.1038/cr.2011.74

Cited by 23 publications

(10 citation statements)

References 55 publications

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“…The transfer of Th17 cells (in vitro-differentiated) into prediabetic mice resulted in the development of sustained hyperglycemia whereas naïve T cells had no effect. The administration of neutralizing anti-IL-17 antibody, but not anti-IFN-γ, after the transfer of Th17 cells impaired the disease development, suggesting an important role of Th17 cell function in STZ-induced diabetes model [50]. In accordance with this, our research group reported recently the important role of Th17 cells during the early stages of diabetes development in STZ model using mice lacking the expression of IL-17 receptor.…”

Section: Van Et Al [71]supporting

confidence: 73%

Th17 cell-Mediated Responses in Type 1 Diabetes Pathogenesis

J.N.U¹

2013

J Clin Cell Immunol

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Type 1 diabetes (T1D) is an autoimmune disease characterized by a selective destruction of insulin-producing pancreatic beta cells. In general, Th1 cytokines are involved in the development of autoimmune diseases, whereas Th2 and regulatory cytokines result in disease prevention. More recently, a new population of IL-17-producing CD4+ T cells has been proposed to represent a distinct T helper cell lineage, named Th17 cells. Th17 cells are critically involved in the development of many autoimmune diseases; however, the exact role of this T cell subset in T1D pathogenesis remains controversial. Here, we review the conflicting evidences about a possible participation of Th17 cells in T1D development and progression, both in diabetic patients and experimental diabetes models.

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Section: Van Et Al [71]supporting

confidence: 73%

Th17 cell-Mediated Responses in Type 1 Diabetes Pathogenesis

J.N.U¹

2013

J Clin Cell Immunol

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“…Although at high doses this agent has diabetogenic potential, due to its capacity to selectively promote death of insulin-producing b cells by apoptosis or necrosis, at low doses STZ generates hydrogen peroxide (50), and induces expression of the glutamic acid decarboxylase autoantigen (51). T1D is an autoimmune condition traditionally associated with Th1 populations (52), but in recent years, multiple low doses of STZinduced T1D demonstrated the involvement of Th17 cells in the pathogenesis of T1D (53), and therapeutic strategies designed to inhibit these cells are likely to be applicable in T1D (54). In EAE, we found that clopidogrel and ticagrelor affect the development of Th17 but not Th1, so we investigated the model of TNBSinduced colitis and multiple low-dose STZ-induced T1D with the antagonists.…”

Section: Discussionmentioning

confidence: 99%

Critical Role of P2Y12 Receptor in Regulation of Th17 Differentiation and Experimental Autoimmune Encephalomyelitis Pathogenesis

Chen

Zhou

Gao

et al. 2017

The Journal of Immunology

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Adenosine 5'-diphosphate is a key endogenous cell-signaling molecule that can activate P2 purinergic receptor family members. ADP-P2Y signaling is reported to be associated with inflammation, but its function in T cell differentiation and autoimmune diseases pathogenesis is unclear. In this study, we found that the P2Y receptor was upregulated in the peripheral immune tissues of experimental autoimmune encephalomyelitis (EAE) mice. Deficiency of P2Y led to a reduced peak severity and cumulative disease score in EAE mice, followed by a dramatic reduction of leukocyte infiltration and less extensive demyelination. The percentage of Th17, one of the main pathogenic T cells in EAE, was sharply decreased in P2Y knockout mice, accompanied by decreased IL-17A production and a low mRNA level of Th17-related genes. In vitro culture assay further verified that P2Y directly regulated Th17 differentiation. More interestingly, clopidogrel and ticagrelor, two P2Y-specific antagonists, effectively alleviated the disease severity of EAE and inhibited Th17 differentiation both in vivo and in vitro. Further study demonstrated that blocking the P2Y receptor also ameliorated the symptoms of 2,4,6-trinitrobenzenesulfonic acid-induced colitis and multiple low-dose streptozocin-induced type 1 diabetes. Our findings not only revealed the critical role of P2Y in Th17 differentiation and EAE pathogenesis, but also suggested the promising potential of P2Y antagonists in the treatment of autoimmune diseases.

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“…Moreover, it was reported that T cell vaccination (TCV) treatment inhibits autoimmune diabetes induced by multiple low-dose streptozotocin (MLD-STZ) in mice through the suppression of intrapancreatic Th17 cells through inhibition of STAT3-mediated RORgt activation [ 63 ]. Administration of B7-H4-immunoglobulin fusion protein (B7-H4.Ig), a newly identified T cell coinhibitory signaling molecule, blocks the onset of diabetes in NOD mice [ 64 ].…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

Th17 Cells in Type 1 Diabetes: Role in the Pathogenesis and Regulation by Gut Microbiome

Liu

Chu

2015

Mediators of Inflammation

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Type 1 diabetes (T1D) is an autoimmune disease which is characterized by progressive destruction of insulin producing pancreatic islet β cells. The risk of developing T1D is determined by both genetic and environmental factors. A growing body of evidence supports an important role of T helper type 17 (Th17) cells along with impaired T regulatory (Treg) cells in the development of T1D in animal models and humans. Alteration of gut microbiota has been implicated to be responsible for the imbalance between Th17 and Treg cells. However, there is controversy concerning a pathogenic versus protective role of Th17 cells in murine models of diabetes in the context of influence of gut microbiota. In this review we will summarize current knowledge about Th17 cells and gut microbiota involved in T1D and propose Th17 targeted therapy in children with islet autoimmunity to prevent progression to overt diabetes.

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T-cell vaccination leads to suppression of intrapancreatic Th17 cells through Stat3-mediated RORγt inhibition in autoimmune diabetes

Cited by 23 publications

References 55 publications

Th17 cell-Mediated Responses in Type 1 Diabetes Pathogenesis

Th17 cell-Mediated Responses in Type 1 Diabetes Pathogenesis

Critical Role of P2Y12 Receptor in Regulation of Th17 Differentiation and Experimental Autoimmune Encephalomyelitis Pathogenesis

Th17 Cells in Type 1 Diabetes: Role in the Pathogenesis and Regulation by Gut Microbiome

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