Capicua deficiency induces autoimmunity and promotes follicular helper T cell differentiation via derepression of ETV5

Abstract

High-affinity antibody production through the germinal centre (GC) response is a pivotal process in adaptive immunity. Abnormal development of follicular helper T (T(FH)) cells can induce the GC response to self-antigens, subsequently leading to autoimmunity. Here we show the transcriptional repressor Capicua/CIC maintains peripheral immune tolerance by suppressing aberrant activation of adaptive immunity. CIC deficiency induces excessive development of T(FH) cells and GC responses in a T-cell-intrinsic manner. ETV5 expression is derepressed in Cic null T(FH) cells and knockdown of Etv5 suppresses the enhanced T(FH) cell differentiation in Cic-deficient CD4+ T cells, suggesting that Etv5 is a critical CIC target gene in T(FH) cell differentiation. Furthermore, we identify Maf as a downstream target of the CIC-ETV5 axis in this process. These data demonstrate that CIC maintains T-cell homeostasis and negatively regulates T(FH) cell development and autoimmunity.