AP-1-independent NFAT signaling maintains follicular T cell function in infection and autoimmunity

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. Follicular T helper (Tfh) cells coordinate optimal germinal center responses, but abnormal Tfh cell function contributes to autoantibody-dependent autoimmunity. Seth et al. demonstrate that AP-1-independent NFAT gene expression, typically associated with hyporesponsive T cells, is required for Tfh cell maintenance and is a therapeutic target in murine lupus.

Automated summary

Coordinated gene expression programs play a crucial role in T cell subset development and function. This study reveals that NFAT gene expression, typically associated with hyporesponsive T cell states, is also a distinguishing feature of Tfh cells. Disruption of NFAT signaling specifically impacts Tfh cell maintenance and has therapeutic potential for autoantibody-dependent autoimmunity.