1. Extraislet expression of islet antigen boosts T cell exhaustion to partially prevent autoimmune diabetes.
- Author
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Selck C, Jhala G, De George DJ, Kwong CJ, Christensen MK, Pappas EG, Liu X, Ge T, Trivedi P, Kallies A, Thomas HE, Kay TWH, and Krishnamurthy B
- Subjects
- Mice, Animals, Proteins metabolism, T-Cell Exhaustion, Glucose-6-Phosphatase genetics, Glucose-6-Phosphatase metabolism, Mice, Transgenic, Mice, Inbred NOD, CD8-Positive T-Lymphocytes, Diabetes Mellitus, Type 1 genetics, Diabetes Mellitus, Type 1 prevention & control, Islets of Langerhans metabolism
- Abstract
Persistent antigen exposure results in the differentiation of functionally impaired, also termed exhausted, T cells which are maintained by a distinct population of precursors of exhausted T (T
PEX ) cells. T cell exhaustion is well studied in the context of chronic viral infections and cancer, but it is unclear whether and how antigen-driven T cell exhaustion controls progression of autoimmune diabetes and whether this process can be harnessed to prevent diabetes. Using nonobese diabetic (NOD) mice, we show that some CD8+ T cells specific for the islet antigen, islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) displayed terminal exhaustion characteristics within pancreatic islets but were maintained in the TPEX cell state in peripheral lymphoid organs (PLO). More IGRP-specific T cells resided in the PLO than in islets. To examine the impact of extraislet antigen exposure on T cell exhaustion in diabetes, we generated transgenic NOD mice with inducible IGRP expression in peripheral antigen-presenting cells. Antigen exposure in the extraislet environment induced severely exhausted IGRP-specific T cells with reduced ability to produce interferon (IFN)γ, which protected these mice from diabetes. Our data demonstrate that T cell exhaustion induced by delivery of antigen can be harnessed to prevent autoimmune diabetes., Competing Interests: Competing interests statement:The authors declare no competing interest.- Published
- 2024
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