Peng Zixuan, Nagarajan Vijayaraj, Horai Reiko, Jittayasothorn Yingyos, Mattapallil Mary J, Caspi Rachel R
Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD, USA; Eye Center of Xiangya Hospital, Central South University, Changsha, Hunan, China.
Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
Cell Rep. 2025 Jun 24;44(6):115780. doi: 10.1016/j.celrep.2025.115780. Epub 2025 May 30.
Despite ocular immune privilege, circulating retina-specific T cells can trigger autoimmune uveitis, yet intraocular bleeding-a relatively common event-rarely leads to disease. Using an in vivo immune privilege model, we previously reported that all naive retina-specific T cells entering the eye become primed in situ; about 30% become Foxp3 regulatory T cells (Tregs), while the rest fail to induce pathology. Here, single-cell transcriptomics and functional validation revealed distinct phenotypes in both populations: ocular Tregs were highly suppressive, whereas non-Tregs expressed suppression- and anergy-associated genes and lacked regulatory function. Trajectory analyses suggested that Tregs and anergic cells arise from a common proliferative precursor in parallel, rather than sequentially. Our data indicate a key checkpoint governing the divergence of anergic and regulatory fates. These findings provide molecular-level insights into ocular immune privilege and may inform strategies to silence autoimmune effector cells or reverse T cell unresponsiveness in cancer, vaccination, or chronic infection.
尽管存在眼部免疫赦免，但循环中的视网膜特异性T细胞可引发自身免疫性葡萄膜炎，然而眼内出血（一种相对常见的情况）很少导致疾病。利用体内免疫赦免模型，我们之前报道所有进入眼睛的初始视网膜特异性T细胞都会在原位被激活；约30%会成为Foxp3调节性T细胞（Tregs），而其余细胞则不会诱发病变。在此，单细胞转录组学和功能验证揭示了这两个群体的不同表型：眼部Tregs具有高度抑制性，而非Tregs表达与抑制和无反应相关的基因且缺乏调节功能。轨迹分析表明Tregs和无反应性细胞平行地而非顺序地源自共同的增殖前体。我们的数据表明存在一个控制无反应性和调节性命运分歧的关键检查点。这些发现为眼部免疫赦免提供了分子水平的见解，并可能为在癌症、疫苗接种或慢性感染中使自身免疫效应细胞失活或逆转T细胞无反应性的策略提供依据。
