16: MIR-17 ∼ 92 promotes T follicular helper cell differentiation and represses subset-inappropriate gene expression

T follicular helper (Tfh) cells are the prototypic T helper cell subset specialized to enable B cells to form germinal centers (GCs) and produce high affinity antibodies. Tfh cell differentiation begins very early in the immune response, coinciding with rapid proliferation that expands the pool of responding cells. Here we show that T cells lacking all microRNAs completely failed to differentiate into Tfh cells in vivo. MicroRNA-deficient T cells exhibited impaired proliferation as expected, but they also displayed an independent defect in the induction of the functionally critical Tfh cell proteins BCL6 and CXCR5. We found that the miR-17 ∼ 92 cluster was required for robust Tfh cell differentiation and function in a cell intrinsic manner that also occurred regardless of changes in proliferation. Conversely, miR-17 ∼ 92 overexpression in T cells promoted Tfh cell differentiation and GC B cell induction. Early in the response to protein antigen, these effects were partially dependent on altered expression of the miR-17 ∼ 92 target gene Pten , a known inhibitor of Tfh cell differentiation. In a viral infection model, Tfh cells depended on the miR-17 ∼ 92 cluster to restrain the expression of Tfh subset-inappropriate genes, including Ccr6, Il1r2, Il1r1, and the cytokine Il22. Conserved regions in the RAR-related orphan receptor alpha ( Rora ) 3’ UTR were directly targeted by all 4 miRNA families in the cluster. Genetically removing one Rora allele significantly rescued the inappropriate gene expression 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.