Repression of miR-31 by BCL6 stabilizes the helper function of human follicular helper T cells

Follicular helper T cells (T_FHs) are a key component of adaptive immune responses as they help antibody production by B cells. Differentiation and function of T_FH cells are controlled by the master gene BCL6, but it is largely unclear how this transcription repressor specifies the T_FH program. Here we asked whether BCL6 controlled helper function through down-regulation of specific microRNAs (miRNAs). We first assessed miRNA expression in T_FH cells and defined a T_FH-specific miRNA signature. We report that hsa-miR-31-5p (miR-31) is down-regulated in T_FH; we showed that BCL6 suppresses miR-31 expression by binding to its promoter; and we demonstrated that miR-31 inhibits the expression of molecules that control T-helper function, such as CD40L and SAP. These findings identify a BCL6-initiated inhibitory circuit that stabilizes the follicular helper T cell program at least in part through the control of miRNA transcription. Although BCL6 controls T_FH activity in human and mouse, the role of miR-31 is restricted to human T_FH cell differentiation, reflecting a species specificity of the miR-31 action. Our findings highlight miR-31 as a possible target to modulate human T cell dependent antibody responses in the settings of infection, vaccination, or immune dysregulation.