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MicroRNA-146a regulates ICOS–ICOSL signalling to limit accumulation of T follicular helper cells and germinal centres

Author

Listed:
  • Alvin Pratama

    (John Curtin School of Medical Research, Australian National University, Building 131, Garran Road, Canberra, Australian Capital Territory 0200, Australia)

  • Monika Srivastava

    (John Curtin School of Medical Research, Australian National University, Building 131, Garran Road, Canberra, Australian Capital Territory 0200, Australia)

  • Naomi J. Williams

    (John Curtin School of Medical Research, Australian National University, Building 131, Garran Road, Canberra, Australian Capital Territory 0200, Australia)

  • Ilenia Papa

    (John Curtin School of Medical Research, Australian National University, Building 131, Garran Road, Canberra, Australian Capital Territory 0200, Australia)

  • Sau K. Lee

    (John Curtin School of Medical Research, Australian National University, Building 131, Garran Road, Canberra, Australian Capital Territory 0200, Australia)

  • Xuyen T. Dinh

    (Comparative Genomics Centre, James Cook University)

  • Andreas Hutloff

    (Chronic Immune Reactions Group, German Rheumatism Research Centre Berlin (DRFZ), a Leibniz Institute)

  • Margaret A. Jordan

    (Comparative Genomics Centre, James Cook University)

  • Jimmy L. Zhao

    (California Institute of Technology)

  • Rafael Casellas

    (Genomics and Immunity Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health)

  • Vicki Athanasopoulos

    (John Curtin School of Medical Research, Australian National University, Building 131, Garran Road, Canberra, Australian Capital Territory 0200, Australia)

  • Carola G. Vinuesa

    (John Curtin School of Medical Research, Australian National University, Building 131, Garran Road, Canberra, Australian Capital Territory 0200, Australia)

Abstract

Tight control of T follicular helper (Tfh) cells is required for optimal maturation of the germinal centre (GC) response. The molecular mechanisms controlling Tfh-cell differentiation remain incompletely understood. Here we show that microRNA-146a (miR-146a) is highly expressed in Tfh cells and peak miR-146a expression marks the decline of the Tfh response after immunization. Loss of miR-146a causes cell-intrinsic accumulation of Tfh and GC B cells. MiR-146a represses several Tfh-cell-expressed messenger RNAs, and of these, ICOS is the most strongly cell autonomously upregulated target in miR-146a-deficient T cells. In addition, miR-146a deficiency leads to increased ICOSL expression on GC B cells and antigen-presenting cells. Partial blockade of ICOS signalling, either by injections of low dose of ICOSL blocking antibody or by halving the gene dose of Icos in miR-146a-deficient T cells, prevents the Tfh and GC B-cell accumulation. Collectively, miR-146a emerges as a post-transcriptional brake to limit Tfh cells and GC responses.

Suggested Citation

  • Alvin Pratama & Monika Srivastava & Naomi J. Williams & Ilenia Papa & Sau K. Lee & Xuyen T. Dinh & Andreas Hutloff & Margaret A. Jordan & Jimmy L. Zhao & Rafael Casellas & Vicki Athanasopoulos & Carol, 2015. "MicroRNA-146a regulates ICOS–ICOSL signalling to limit accumulation of T follicular helper cells and germinal centres," Nature Communications, Nature, vol. 6(1), pages 1-14, May.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7436
    DOI: 10.1038/ncomms7436
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