Department of Pediatrics, Section of Diabetes and Endocrinology.
Program in Developmental Biology.
JCI Insight. 2018 Jan 25;3(2). doi: 10.1172/jci.insight.97322.
T cell receptor (TCR) affinity is a critical factor of Treg lineage commitment, but whether self-reactivity is a determining factor in peripheral Treg function remains unknown. Here, we report that a high degree of self-reactivity is crucial for tissue-specific Treg function in autoimmunity. Based on high expression of CD5, we identified a subset of self-reactive Tregs expressing elevated levels of T-bet, GITR, CTLA-4, and ICOS, which imparted significant protection from autoimmune diabetes. We observed that T-bet expression in Tregs, necessary for control of Th1 autoimmunity, could be induced in an IFNγ-independent fashion and, unlike in conventional T cells (Tconv), was strongly correlated with the strength of TCR signaling. The level of CD5 similarly identified human Tregs with an increased functional profile, suggesting that CD5hi Tregs may constitute an efficacious subpopulation appropriate for use in adoptive Treg therapies for treatment of inflammatory conditions. Overall, this work establishes an instrumental role of high TCR self-reactivity in driving Treg function.
T 细胞受体 (TCR) 亲和力是 Treg 谱系分化的关键因素，但自身反应性是否是外周 Treg 功能的决定因素尚不清楚。在这里，我们报告称，高度的自身反应性对于自身免疫中的组织特异性 Treg 功能至关重要。基于 CD5 的高表达，我们鉴定出了一个表达高水平 T-bet、GITR、CTLA-4 和 ICOS 的自身反应性 Treg 亚群，这为自身免疫性糖尿病提供了显著的保护。我们观察到，Tregs 中控制 Th1 自身免疫所必需的 T-bet 表达可以以 IFNγ 非依赖性的方式被诱导，并且与传统 T 细胞 (Tconv) 不同，它与 TCR 信号的强度强烈相关。类似地，CD5 的水平也鉴定出了具有增强功能谱的人源 Treg，提示 CD5hi Treg 可能构成一种有效的亚群，适合用于过继性 Treg 治疗以治疗炎症性疾病。总的来说，这项工作确立了高 TCR 自身反应性在驱动 Treg 功能中的重要作用。
