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

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 and Carola G. Vinuesa ()
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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

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7436

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