Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
J Exp Med. 2012 Feb 13;209(2):243-50. doi: 10.1084/jem.20111174. Epub 2012 Jan 23.
Follicular helper T cells (T(FH) cells) constitute the CD4(+) T cell subset that is specialized to provide help to germinal center (GC) B cells and, consequently, mediate the development of long-lived humoral immunity. T(FH) cell differentiation is driven by the transcription factor Bcl6, and recent studies have identified cytokine and cell-cell signals that drive Bcl6 expression. However, although T(FH) dysregulation is associated with several major autoimmune diseases, the mechanisms underlying the negative regulation of T(FH) cell differentiation are poorly understood. In this study, we show that STAT5 inhibits T(FH) cell differentiation and function. Constitutive STAT5 signaling in activated CD4(+) T cells selectively blocked T(FH) cell differentiation and GCs, and IL-2 signaling was a primary inducer of this pathway. Conversely, STAT5-deficient CD4(+) T cells (mature STAT5(fl/fl) CD4(+) T cells transduced with a Cre-expressing vector) rapidly up-regulated Bcl6 expression and preferentially differentiated into T(FH) cells during T cell priming in vivo. STAT5 signaling failed to inhibit T(FH) cell differentiation in the absence of the transcription factor Blimp-1, a direct repressor of Bcl6 expression and T(FH) cell differentiation. These results demonstrate that IL-2, STAT5, and Blimp-1 collaborate to negatively regulate T(FH) cell differentiation.
滤泡辅助 T 细胞（T(FH) 细胞）构成了专门为生发中心（GC）B 细胞提供帮助的 CD4(+)T 细胞亚群，从而介导了长期体液免疫的发展。T(FH) 细胞分化由转录因子 Bcl6 驱动，最近的研究已经确定了驱动 Bcl6 表达的细胞因子和细胞间信号。然而，尽管 T(FH) 细胞失调与几种主要的自身免疫性疾病有关，但 T(FH) 细胞分化的负调控机制仍知之甚少。在这项研究中，我们表明 STAT5 抑制 T(FH) 细胞分化和功能。在激活的 CD4(+)T 细胞中组成型 STAT5 信号选择性地阻断了 T(FH) 细胞分化和 GC 的形成，而 IL-2 信号是该途径的主要诱导剂。相反，STAT5 缺陷型 CD4(+)T 细胞（成熟 STAT5(fl/fl)CD4(+)T 细胞转导表达 Cre 的载体）在体内 T 细胞初始化过程中迅速上调 Bcl6 表达，并优先分化为 T(FH) 细胞。在缺乏转录因子 Blimp-1 的情况下，STAT5 信号无法抑制 T(FH) 细胞分化，Blimp-1 是 Bcl6 表达和 T(FH) 细胞分化的直接抑制剂。这些结果表明，IL-2、STAT5 和 Blimp-1 协同负调控 T(FH) 细胞分化。
