Tracking the role of Aire in immune tolerance to the eye with a TCR transgenic mouse model

• 成果类型: Article
• 署名作者: Yin, Mianmian; Smith, Jennifer A.; Chou, Marissa; Chan, Jackie; Jittayasothorn, Yingyos; Gould, Douglas B.; Caspi, Rachel R.; Anderson, Mark S.; Defranco, Anthony L.
• 署名单位: University of California System; University of California San Francisco; University of California System; University of California San Francisco; National Institutes of Health (NIH) - USA; NIH National Eye Institute (NEI); University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12148
• DOI: 10.1073/pnas.2311487121
• 发表日期: 2024-01-30
• 关键词: lyn kinase; spontaneous autoimmunity; dendritic cells; t-cells; mice; expression; mechanisms; initiation

摘要

Roughly one - half of mice with partial defects in two immune tolerance pathways (AireGW/+Lyn-/- mice) spontaneously develop severe damage to their retinas due to T cell reactivity to Aire- regulated interphotoreceptor retinoid-binding protein (IRBP). Single - cell T cell receptor (TCR) sequencing of CD4+ T cells specific for a predominate epitope of IRBP showed a remarkable diversity of autoantigen- specific TCRs with greater clonal expansions in mice with disease. TCR transgenic mice made with an expanded IRBP- specific TCR (P2.U2) of intermediate affinity exhibited strong but incomplete negative selection of thymocytes. This negative selection was absent in IRBP-/- mice and greatly defective in AireGW/+ mice. Most P2.U2+/- mice and all P2.U.2+/-AireGW/+ mice rapidly developed inflammation of the retina and adjacent uvea (uveitis). Aire- dependent IRBP expression in the thymus also promoted Treg differentiation, but the niche for this fate determination was small, suggesting differences in antigen presentation leading to negative selection vs. thymic Treg differentiation and a stronger role for negative selection in preventing autoimmune disease in the retina.