Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
J Exp Med. 2014 Jan 13;211(1):137-51. doi: 10.1084/jem.20131019. Epub 2013 Dec 30.
Regulatory T cells (Treg cells) control different aspects of immune responses, but how the effector functions of Treg cells are regulated is incompletely understood. Here we identified TNF receptor-associated factor 3 (TRAF3) as a regulator of Treg cell function. Treg cell-specific ablation of TRAF3 impaired CD4 T cell homeostasis, characterized by an increase in the Th1 type of effector/memory T cells. Moreover, the ablation of TRAF3 in Treg cells resulted in increased antigen-stimulated activation of follicular T helper cells (TFH cells), coupled with heightened formation of germinal centers and production of high-affinity IgG antibodies. Although the loss of TRAF3 did not reduce the overall frequency of Treg cells, it attenuated the antigen-stimulated production of follicular Treg cells (TFR cells). TRAF3 signaling in Treg cells was required to maintain high level expression of inducible co-stimulator (ICOS), which in turn was required for TFR cell generation and inhibition of antibody responses. These findings establish TRAF3 as a mediator of Treg cell function in the regulation of antibody responses and suggest a role for TRAF3 in mediating ICOS expression in Treg cells.
调节性 T 细胞（Treg 细胞）控制着免疫反应的不同方面，但 Treg 细胞效应功能的调节机制尚不完全清楚。在这里，我们鉴定出 TNF 受体相关因子 3（TRAF3）是 Treg 细胞功能的调节因子。Treg 细胞特异性敲除 TRAF3 会损害 CD4 T 细胞的稳态，表现为 Th1 型效应记忆 T 细胞增加。此外，Treg 细胞中 TRAF3 的缺失导致抗原刺激激活滤泡辅助性 T 细胞（TFH 细胞）增加，与生发中心的形成和高亲和力 IgG 抗体的产生增加有关。虽然 TRAF3 的缺失并没有减少 Treg 细胞的总体频率，但它削弱了抗原刺激产生滤泡调节性 T 细胞（TFR 细胞）。Treg 细胞中的 TRAF3 信号传导对于维持诱导共刺激分子（ICOS）的高表达是必需的，而 ICOS 的表达对于 TFR 细胞的生成和抗体反应的抑制又是必需的。这些发现确立了 TRAF3 作为调节抗体反应中 Treg 细胞功能的介质，并提示 TRAF3 在介导 Treg 细胞中 ICOS 表达中的作用。
