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

Abstract

Follicular helper T cells (Ts) are a key component of adaptive immune responses as they help antibody production by B cells. Differentiation and function of T cells are controlled by the master gene , but it is largely unclear how this transcription repressor specifies the T program. Here we asked whether BCL6 controlled helper function through down-regulation of specific microRNAs (miRNAs). We first assessed miRNA expression in T cells and defined a T-specific miRNA signature. We report that hsa-miR-31-5p (miR-31) is down-regulated in T; 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 activity in human and mouse, the role of miR-31 is restricted to human T 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.

MicroRNA‐mediated regulation of T follicular helper and T follicular regulatory cell identity

“…65 In accordance with that, miR-31 is expressed lower in Tfh cells and 65 In accordance with that, miR-31 is expressed lower in Tfh cells and…”

“…Interestingly, BCL6 also repressed miR-31 expression by binding to its promoter, thereby stabilizing the Tfh cell program. 65 In accordance with that, miR-31 is expressed lower in Tfh cells and Treg cells as compared to naive or effector T cell subsets, 65,152,153 and thus might prevent aberrant transdifferentiation into Tfh,…”

“…63 Once a naive CD4 + T cell becomes activated, this brake is released (by degradation of Ago2 and subsequent reduction in miRNA availability) and the miRNA repertoire of the cell is reprogrammed. 58,60,65,66 However, there are a few miRNAs that overcome global miRNA downregulation by disproportionally increased transcription. 58,60,65,66 However, there are a few miRNAs that overcome global miRNA downregulation by disproportionally increased transcription.…”

“…Treg cells as compared to naive or effector T cell subsets, 65,152,153 and thus might prevent aberrant transdifferentiation into Tfh, …”

“…64 Several studies investigated the function of miRNAs that are highly expressed in naive CD4 + T cells and subsequently downregulated in activated cells, and many of these miRNAs repress lineage commitment and stabilize the naive T cell state. 58,60,65,66 However, there are a few miRNAs that overcome global miRNA downregulation by disproportionally increased transcription. 59,60 These "driver miR-NAs" are upregulated after T cell activation and have emerged as critical factors for proper lineage commitment, differentiation, and function of T cells.…”