MiR-23~27~24–mediated control of humoral immunity reveals a TOX-driven regulatory circuit in follicular helper T cell differentiation

Follicular helper T (T_FH) cells are essential for generating protective humoral immunity. To date, microRNAs (miRNAs) have emerged as important players in regulating T_FH cell biology. Here, we show that loss of miR-23~27~24 clusters in T cells resulted in elevated T_FH cell frequencies upon different immune challenges, whereas overexpression of this miRNA family led to reduced T_FH cell responses. Mechanistically, miR-23~27~24 clusters coordinately control T_FH cells through targeting a network of genes that are crucial for T_FH cell biology. Among them, thymocyte selection–associated HMG-box protein (TOX) was identified as a central transcription regulator in T_FH cell development. TOX is highly up-regulated in both mouse and human T_FH cells in a BCL6-dependent manner. In turn, TOX promotes the expression of multiple molecules that play critical roles in T_FH cell differentiation and function. Collectively, our results establish a key miRNA regulon that maintains optimal T_FH cell responses for resultant humoral immunity.