Aire mediates tolerance to insulin through thymic trimming of high-affinity T cell clones.

Autor:	Smith JA; Diabetes Center, University of California San Francisco, San Francisco, CA 94143., Yuen BTK; Diabetes Center, University of California San Francisco, San Francisco, CA 94143., Purtha W; Diabetes Center, University of California San Francisco, San Francisco, CA 94143., Balolong JM; Diabetes Center, University of California San Francisco, San Francisco, CA 94143., Phipps JD; Diabetes Center, University of California San Francisco, San Francisco, CA 94143., Crawford F; Department of Immunology and Genomic Medicine, National Jewish Health, Denver, CO 80206., Bluestone JA; Sean N. Parker Autoimmune Research Laboratory, Diabetes Center, University of California, San Francisco, CA 94143., Kappler JW; Department of Immunology and Genomic Medicine, National Jewish Health, Denver, CO 80206.; Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.; Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045., Anderson MS; Diabetes Center, University of California San Francisco, San Francisco, CA 94143.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 May 14; Vol. 121 (20), pp. e2320268121. Date of Electronic Publication: 2024 May 06.
DOI:	10.1073/pnas.2320268121
Abstrakt:	Insulin is a central autoantigen in the pathogenesis of T1D, and thymic epithelial cell expression of insulin under the control of the Autoimmune Regulator ( Aire ) is thought to be a key component of maintaining tolerance to insulin. In spite of this general working model, direct detection of this thymic selection on insulin-specific T cells has been somewhat elusive. Here, we used a combination of highly sensitive T cell receptor transgenic models for detecting thymic selection and sorting and sequencing of Insulin-specific CD4+ T cells from Aire-deficient mice as a strategy to further define their selection. This analysis revealed a number of unique t cell receptor (TCR) clones in Aire-deficient hosts with high affinity for insulin/major histocompatibility complex (MHC) ligands. We then modeled the thymic selection of one of these clones in Aire-deficient versus wild-type hosts and found that this model clone could escape thymic negative selection in the absence of thymic Aire. Together, these results suggest that thymic expression of insulin plays a key role in trimming and removing high-affinity insulin-specific T cells from the repertoire to help promote tolerance. Competing Interests: Competing interests statement:The authors declare no competing interest.
Databáze:	MEDLINE
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