Orphan Nuclear Receptor NR2F6 Suppresses T Follicular Helper Cell Accumulation Through Direct Regulation of IL-21

Abstract

CD4 follicular helper T (Tfh) cells are specialized to help B cells during the germinal center reaction and are essential for affinity maturation and long-term humoral immunity. Here we report that loss of the nuclear orphan receptor NR2F6 causes enhanced survival and accumulation of Tfh, GC B and plasma cells following T cell-dependent immunization. Loss of Nr2f6 in CD4 T cells but not B cells is the primary driver of cell accumulation as adoptively transferred Nr2f6-deficient CD4 T cells maintain a larger wild-type host Tfh population through a paracrine effect. Cytokine expression in Nr2f6-deficient CD4 T cells is dysregulated in Tfh cells, in particular, Il21 expression is enhanced. Mechanistically, NR2F6, as a transcription factor, represses interleukin 21 (IL-21) production through direct binding of the Il21 promoter. Disruption of IL-21 signaling reduces Tfh accumulation in Nr2f6-deficient mice. Thus, NR2F6 is a critical negative regulator of Tfh cytokine secretion and prevents excessive Tfh accumulation.