The microRNA cluster miR-17∼92 promotes TFH cell differentiation and represses subset-inappropriate gene expression

Abstract

T follicular helper (TFH) cells are the prototypic helper T cell subset specialized to enable B cells to form germinal centers and produce high-affinity antibodies. We found that miRNA expression by T cells was essential for TFH cell differentiation. More specifically, we show that after protein immunization the microRNA cluster miR-17~92 was critical for robust TFH cell differentiation and function in a cell-intrinsic manner that occurred regardless of changes in proliferation. In a viral infection model, miR-17~92 restrained the expression of TFH subset-inappropriate genes, including the direct target RAR-related orphan receptor alpha (Rora). Genetically removing one Rora allele partially rescued the inappropriate gene signature in miR-17~92-deficient TFH cells. Our results identify the miR-17~92 cluster as a critical regulator of T cell-dependent antibody responses, TFH cell differentiation and the fidelity of the TFH cell gene expression program.