Department of Internal Medicine, Section of Rheumatology, Allergy and Immunology, School of Medicine, Yale University , New Haven, CT, USA.
Department of Immunobiology, School of Medicine, Yale University , New Haven, CT, USA.
J Exp Med. 2023 May 1;220(5). doi: 10.1084/jem.20211110. Epub 2023 Feb 23.
Coordinated gene expression programs enable development and function of T cell subsets. Follicular helper T (Tfh) cells coordinate humoral immune responses by providing selective and instructive cues to germinal center B cells. Here, we show that AP-1-independent NFAT gene expression, a program associated with hyporesponsive T cell states like anergy or exhaustion, is also a distinguishing feature of Tfh cells. NFAT signaling in Tfh cells, maintained by NFAT2 autoamplification, is required for their survival. ICOS signaling upregulates Bcl6 and induces an AP-1-independent NFAT program in primary T cells. Using lupus-prone mice, we demonstrate that genetic disruption or pharmacologic inhibition of NFAT signaling specifically impacts Tfh cell maintenance and leads to amelioration of autoantibody production and renal injury. Our data provide important conceptual and therapeutic insights into the signaling mechanisms that regulate Tfh cell development and function.
协调的基因表达程序使 T 细胞亚群的发育和功能成为可能。滤泡辅助 T（Tfh）细胞通过向生发中心 B 细胞提供选择性和指导性线索来协调体液免疫反应。在这里，我们表明，与无反应性 T 细胞状态（如失能或衰竭）相关的 NFAT 基因表达的 AP-1 非依赖性也是 Tfh 细胞的一个特征。NFAT 信号在 Tfh 细胞中的维持，由 NFAT2 的自动扩增提供，是其存活所必需的。ICOS 信号转导上调 Bcl6，并在原代 T 细胞中诱导一个 AP-1 非依赖性的 NFAT 程序。使用狼疮易感小鼠，我们证明 NFAT 信号的遗传破坏或药理学抑制特异性地影响 Tfh 细胞的维持，并导致自身抗体产生和肾脏损伤的改善。我们的数据为调节 Tfh 细胞发育和功能的信号机制提供了重要的概念和治疗见解。
