miR-17~92 promotes T follicular helper cell differentiation and represses subset-inappropriate gene expression

T follicular helper (T(FH)) 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 T(FH) cell differentiation. More specifically, we show that after protein immunization the microRNA cluster miR-17~92 was critical for robust T(FH) 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 T(FH) 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 T(FH) cells. Our results identify the miR-17~92 cluster as a critical regulator of T cell-dependent antibody responses, T(FH) cell differentiation and the fidelity of the T(FH) cell gene expression program.