Emerging Roles for MicroRNAs in T Follicular Helper Cell Differentiation

T follicular helper (Tfh) cells are essential for the formation of germinal centers (GCs) and the development of long-lived humoral immunity. Tfh cell differentiation is a multistep process driven by the balanced expression of key transcription factors that form a regulatory network in which small changes in gene expression determine the Tfh cell fate decision. Here, we review recent findings that have revealed that certain microRNAs act as important mediators within this network, with roles in tuning gene expression. We integrate these findings into the current understanding of the mechanisms governing T helper cell differentiation, and propose a model in which the establishment of Tfh cell identity is dependent on the differential expression and concerted action of distinct microRNAs and transcription factors.

TrendsT follicular helper (Tfh) cell differentiation is a complex multistep process that involves sequential interactions with dendritic cells (DCs) and B cells.Small changes in gene expression can have an extensive impact on T helper (Th) cell fate decisions and miRNAs critically modulate these processes.Compared with other effector Th cell subsets (e.g., Th1, Th2, Th17), Tfh cells are particularly responsive to regulation by miRNAs, as global miRNA deficiency in CD4+ T cells prevents Tfh cell differentiation.While most miRNAs are downregulated in activated CD4+ T cells, some miRNAs (e.g., the miR-17∼92 cluster, miR-155) are rapidly induced in these cells and contribute to shaping Th cell identity.miR-17∼92 promotes Tfh cell differentiation while at the same time repressing Tfh subset-inappropriate genes.miR-146a is upregulated at later stages during Tfh cell differentiation, acting as a potent inhibitor of Tfh cells.