Abstract
Follicular helper T cells (TFH cells) are the prototypic helper T cell subset specialized to enable B cells to form germinal centers (GCs) and produce high-affinity antibodies. We found that expression of microRNAs (miRNAs) by T cells was essential for TFH cell differentiation. More specifically, we show that after immunization of mice with protein, the miRNA cluster miR-17∼92 was critical for robust differentiation and function of TFH cells in a cell-intrinsic manner that occurred regardless of changes in proliferation. In a viral infection model, miR-17∼92 restrained the expression of genes 'inappropriate' to the TFH cell subset, including the direct miR-17∼92 target Rora. Removal of one Rora allele partially 'rescued' the inappropriate gene signature in miR-17∼92-deficient TFH cells. Our results identify the miR-17∼92 cluster as a critical regulator of T cell–dependent antibody responses, TFH cell differentiation and the fidelity of the TFH cell gene-expression program.
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Acknowledgements
We thank M. Panduro for technical assistance; R. Blelloch (University of California, San Francisco) for Dgcr8fl/fl mice; R. Barbeau, J. Pollack, A. Barczak and D. Erle for assistance with microarray experiments; the 'miRNA in lymphocytes interest group' of the University of California, San Francisco, for discussions; D. Fuentes for animal husbandry; and D. Le for help with genotyping. Supported by the Burroughs Wellcome Fund (CABS 1006173 to K.M.A.), the US National Institutes of Health (R01 HL109102 and P01 HL107202 to K.M.A.; P01 AI35297 and U19 AI056388 to J.A.B.; and P30 DK63720 for core support), Juvenile Diabetes Research Foundation (J.A.B.), the Swiss National Science Foundation (PBBEP3-133516 to D.B.), the Swiss Foundation for Grants in Biology and Medicine (PASMP3-142725 to D.B.; and PASMP3-124274/1 to L.T.J.), the National Science Foundation (J.M.C.) and the Wellcome Trust (O.B.).
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D.B. did and analyzed most of the experiments; R.K., J.M.C., M.M.M., S.P., D.d.K., O.B., M.M. and L.T.J. did and analyzed some of the experiments; J.A.B. interpreted the data; D.B., K.M.A. and L.T.J. designed the experiments, interpreted the data, and wrote the manuscript; and all authors discussed the results and commented on the manuscript.
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Baumjohann, D., Kageyama, R., Clingan, J. et al. The microRNA cluster miR-17∼92 promotes TFH cell differentiation and represses subset-inappropriate gene expression. Nat Immunol 14, 840–848 (2013). https://doi.org/10.1038/ni.2642
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DOI: https://doi.org/10.1038/ni.2642
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