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Differentiating MHC-dependent and -independent mechanisms of lymph node stromal cell regulation of proinsulin-specific CD8+ T-cells in type 1 diabetes

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posted on 29.10.2020, 14:46 by Ada Admin, Terri C. Thayer, Joanne Davies, James A. Pearson, Stephanie J. Hanna, Li Wen, F. Susan Wong
Lymph node stromal cells (LNSC) are essential for providing and maintaining peripheral self-tolerance of potentially autoreactive cells. In type 1 diabetes, proinsulin-specific CD8+T-cells, escaping central and peripheral tolerance, contribute to beta-cell destruction. Using G9Cα-/-CD8+T-cells specific for proinsulin, we studied the mechanisms by which LNSC regulate low-avidity autoreactive cells in the nonobese diabetic (NOD) mouse model of type 1 diabetes. Whereas MHC-matched NOD-LNSC significantly reduced G9Cα-/-CD8+T-cell cytotoxicity and DC-induced proliferation, they failed to sufficiently regulate T-cells stimulated by anti-CD3/CD28. In contrast, non-MHC matched, control C57BL/6 mouse LNSC suppressed T-cell receptor engagement by anti-CD3/CD28 via MHC-independent mechanisms. This C57BL/6-LNSC suppression was maintained even after removal of the LNSC, demonstrating a direct effect of LNSC on T-cells, modifying antigen sensitivity and effector function. Thus, our results suggest that a loss of NOD-LNSC MHC-independent suppressive mechanisms may contribute to diabetes development.

Funding

The work was supported by a post-doctoral fellowship from JDRF (3-PDF-2014-211-A-N) to TCT and funding from the Medical Research Council (UK) MR/K021141/1 to FSW.

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