PT  - JOURNAL ARTICLE
AU  - Thayer, Terri C.
AU  - Davies, Joanne
AU  - Pearson, James A.
AU  - Hanna, Stephanie J.
AU  - Wen, Li
AU  - Wong, F. Susan
TI  - Differentiating MHC-Dependent and -Independent Mechanisms of Lymph Node Stromal Cell Regulation of Proinsulin-Specific CD8<sup>+</sup> T-Cells in type 1 Diabetes
AID  - 10.2337/db19-1050
DP  - 2020 Oct 28
TA  - Diabetes
PG  - db191050
4099  - http://diabetes.diabetesjournals.org/content/early/2020/10/28/db19-1050.short
4100  - http://diabetes.diabetesjournals.org/content/early/2020/10/28/db19-1050.full
AB  - 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.