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Original Research
Differentiating MHC-Dependent and -Independent Mechanisms of Lymph Node Stromal Cell Regulation of Proinsulin-Specific CD8+ T-Cells in type 1 Diabetes
Terri C. Thayer, Joanne Davies, James A. Pearson, Stephanie J. Hanna, Li Wen, F. Susan Wong
Diabetes 2020 Oct; db191050. https://doi.org/10.2337/db19-1050
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Abstract

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.

Footnotes

  • This article contains supplementary material online at https://doi.org/10.2337/figshare.13146209.

  • Received October 17, 2019.
  • Accepted October 26, 2020.
  • © 2020 by the American Diabetes Association
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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
Terri C. Thayer, Joanne Davies, James A. Pearson, Stephanie J. Hanna, Li Wen, F. Susan Wong
Diabetes Oct 2020, db191050; DOI: 10.2337/db19-1050

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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
Terri C. Thayer, Joanne Davies, James A. Pearson, Stephanie J. Hanna, Li Wen, F. Susan Wong
Diabetes Oct 2020, db191050; DOI: 10.2337/db19-1050
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