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

• 成果类型: Article
• 署名作者: Smith, Jennifer A.; Yuen, Benjamin T. K.; Purtha, Whitney; Balolong, Jared M.; Phipps, Jonah D.; Crawford, Frances; Bluestone, Jeffrey A.; Kappler, John W.; Anderson, Mark S.
• 署名单位: University of California System; University of California San Francisco; National Jewish Health; University of California System; University of California San Francisco; University of Colorado System; University of Colorado Anschutz Medical Campus; University of Colorado System; University of Colorado Anschutz Medical Campus
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12824
• DOI: 10.1073/pnas.2320268121
• 发表日期: 2024-05-14
• 关键词: nonobese diabetic mice; proinsulin epitopes; gene-expression; peptide; autoantigen; recognize; specificity; mutations; responses; genotype

摘要

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 insulinspecific 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 Airedeficient mice as a strategy to further define their selection. This analysis revealed a number of unique t cell receptor (TCR) clones in Airedeficient hosts with high affinity for insulin/major histocompatibility complex (MHC) ligands. We then modeled the thymic selection of one of these clones in Airedeficient 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 insulinspecific T cells from the repertoire to help promote tolerance.