Characterization and Modulation of Autoreactive CD4+ T cells in Type 1 Diabetes Public Deposited

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  • March 20, 2019
Creator
  • Li, Li
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • Type 1 diabetes (T1D) is an autoimmune disease mediated by pathogenic β cell-specific T cells. The soluble (s) IAg7- immunoglobulin (Ig) dimers covalently linked to GAD65 peptides or the mimetic BDC2.5 epitope (mBDC) were utilized in two studies. The first use was to enhance the efficacy of peptide treatment. NOD female mice with established β cell autoimmunity received a short course of sIAg7-Ig dimers intravenously (i.v.). NOD mice treated with sIAg7-mBDC continued to develop diabetes. In marked contrast, the majority of NOD mice treated with sIAg7-Ig complexed with the GAD65-specific peptides p217 or p286 remained diabetes-free. Protection correlated with an increased frequency of IL-10 secreting immunoregulatory CD4+ T cells that delayed diabetes in a co-adoptive transfer model. These results demonstrate that treatment with a short-course of sIAg7-GAD65 peptide dimers is an effective approach to suppress T1D. Secondly, the relative role for BDC2.5 clonotypic CD4+ T cells in the progression of the diabetogenic response was tracked and temporal analyzed using sIAg7-mBDC multimers. The frequency and/or number of T cells binding sIAg7-mBDC multimers (g7-mBDC+) increase with in peripheral blood lymphocytes (PBL) and the islets at the onset of β cell autoimmunity in NOD female mice. In contrast, a reduced frequency and number of g7-mBDC+ T cells was observed in the PBL and islets of NOD male mice. T cell receptor (TCR) variable β (Vβ) gene complementary determinant region 3 (CDR3) sequences revealed that BDC2.5 clonotypic CD4+ T cells in the islets but not PBL selectively expressed TRBV15. These data demonstrate that g7-mBDC+ T cells are an early indicator of the development of destructive insulitis, and that both clonotypic expansion and preferential usage of TCR characterize islet infiltrating g7-mBDC+ T cells.
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  • Tisch, Roland
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