A miR-23~27~24 regulon that controls follicular helper T cell differentiation

Follicular helper T (Tfh) cells are essential for generating protective humoral immunity. To date, microRNAs (miRNAs) have emerged as important players in regulating Tfh cell biology. Here, we show that loss of miR-23~27~24 clusters in T cells resulted in elevated Tfh cell frequencies upon different immune challenges whereas overexpression of this miRNA family led to reduced Tfh cell responses. Mechanistically, miR-23~27~24 clusters coordinately control Tfh cells through targeting a network of genes that are crucial for Tfh cell biology. Among them, thymocyte selection-associated HMG-box protein (TOX) was identified as a central transcription regulator in Tfh cell development. TOX is highly up-regulated in both mouse and human Tfh cells in a BCL6-dependent manner. In turn, TOX promotes the expression of multiple molecules that play critical roles in Tfh cell differentiation and function. Collectively, our study on miR-23~27~24-mediated control of humoral immunity reveals a TOX-driven regulatory circuit in orchestrating Tfh cell responses. Overall design: CD44-CD4+ naive T cells (Tn), CD44+PSGL1hiCXCR5-CD4+ T cells (Th1), CD44+PSGL1intCXCR5+CD4+ T cells (Tfh) and CD44+PSGL1loCXCR5+CD4+ T cells (GC-Tfh) isolated from LCMV-infected mice with T cell-specific deletion of both miR-23~27~24 clusters or WT littermates