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

  1. S. Abrignania,c,2
  1. aIstituto Nazionale Genetica Molecolare “Romeo ed Enrica Invernizzi,” Milan 20122, Italy;
  2. bDepartment of Otolaryngology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Cà Granda Ospedale Maggiore Policlinico, Milan 20122, Italy;
  3. cDepartment of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan 20122, Italy;
  4. dDepartment of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan 20129, Italy
  1. Edited by Rafi Ahmed, Emory University, Atlanta, GA, and approved October 26, 2017 (received for review March 31, 2017)

Significance

Antibody production by B lymphocytes generally requires help by T follicular helper (TFH) cells, a specific subset of CD4+ T lymphocytes. The function of TFH cells depends on BCL6, a transcriptional repressor whose target genes that account for the helper activity are unknown. By the combined analysis of microRNA (miRNA) and gene expression profiling in human TFH cells, we found that miR-31, a miRNA that inhibits gene transcripts relevant for TFH cells biology, is down-regulated in TFH. BCL6 contributes to “helperness” by shutting down miR-31 gene expression, thus stabilizing the follicular helper T cell program. Thus miR-31 is a therapeutic target to modulate human T cell-dependent antibody responses in immunomediated disorders.

Abstract

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

Footnotes

  • ?1A.R., E.P., and M.L. contributed equally to this work.

  • ?2To whom correspondence may be addressed. Email: abrignani{at}ingm.org or pagani{at}ingm.org.
  • Author contributions: A.R., E.P., M.L., G.R., M.P., and S.A. designed research; A.R., E.P., M.L., M.D.S., S.V., and S.C. performed research; A.R., E.P., M.L., M.D.S., V.R., S.V., S.C., R.J.P.B., L.P., S.T., J.G., G.R., M.P., and S.A. analyzed data; and A.R., E.P., M.L., V.R., G.R., M.P., and S.A. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • Data deposition: The RNA-seq data reported in this paper have been deposited in the European Nucleotide Archive (ENA) (accession no. PRJEB15005).

  • This article contains supporting information online at www.danielhellerman.com/lookup/suppl/doi:10.1073/pnas.1705364114/-/DCSupplemental.

Published under the PNAS license.

Online Impact

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