Differential cell-intrinsic regulations of germinal center B and T cells by miR-146a and miR-146b

Reciprocal interactions between B and follicular T helper (Tfh) cells orchestrate the germinal center (GC) reaction, a hallmark of humoral immunity. Abnormal GC responses could lead to the production of pathogenic autoantibodies and the development of autoimmunity. Here we show that miR-146a control...

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Published in:	Nature communications Vol. 9; no. 1; pp. 2757 - 13
Main Authors:	Cho, Sunglim, Lee, Hyang-Mi, Yu, I-Shing, Choi, Youn Soo, Huang, Hsi-Yuan, Hashemifar, Somaye Sadat, Lin, Ling-Li, Chen, Mei-Chi, Afanasiev, Nikita D., Khan, Aly Azeem, Lin, Shu-Wha, Rudensky, Alexander Y., Crotty, Shane, Lu, Li-Fan
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 16-07-2018 Nature Publishing Group Nature Portfolio
Subjects:	13/1 13/106 13/31 13/95 38/88 38/91 631/250/2152/2153 631/250/2152/2153/1982 631/250/2502 631/250/2502/2055 64/60 82/80 96/109 96/63 Animals Autoantibodies Autoantibodies - biosynthesis Autoimmunity Autoimmunity - genetics B-Lymphocytes - cytology B-Lymphocytes - drug effects B-Lymphocytes - immunology Bone Marrow Cells - cytology Bone Marrow Cells - drug effects Bone Marrow Cells - immunology CD40 antigen CD40 Antigens - genetics CD40 Antigens - immunology Cell Differentiation Clonal deletion Gene Expression Regulation Germinal Center - cytology Germinal Center - drug effects Germinal Center - immunology Germinal centers Humanities and Social Sciences Humoral immunity Immunity Immunity, Humoral - genetics Interleukin-4 - pharmacology Lymphocytes Lymphocytes B Lymphocytes T Mice Mice, Transgenic MicroRNAs - genetics MicroRNAs - immunology Molecular chains multidisciplinary Primary Cell Culture Protein Isoforms - genetics Protein Isoforms - immunology Regulations Science Science (multidisciplinary) Signal transduction Signal Transduction - immunology T-Lymphocytes, Helper-Inducer - cytology T-Lymphocytes, Helper-Inducer - drug effects T-Lymphocytes, Helper-Inducer - immunology
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Summary:	Reciprocal interactions between B and follicular T helper (Tfh) cells orchestrate the germinal center (GC) reaction, a hallmark of humoral immunity. Abnormal GC responses could lead to the production of pathogenic autoantibodies and the development of autoimmunity. Here we show that miR-146a controls GC responses by targeting multiple CD40 signaling pathway components in B cells; by contrast, loss of miR-146a in T cells does not alter humoral responses. However, specific deletion of both miR-146a and its paralog, miR-146b, in T cells increases Tfh cell numbers and enhanced GC reactions. Thus, our data reveal differential cell-intrinsic regulations of GC B and Tfh cells by miR-146a and miR-146b. Together, members of the miR-146 family serve as crucial molecular brakes to coordinately control GC reactions to generate protective humoral responses without eliciting unwanted autoimmunity. In the germinal center (GC), B and T cells interact to induce the production of protective antibodies against threats. Here the authors show that microRNA miR-146a modulates CD40 signaling in GC B cells, while both miR-146a and miR-146b synergize to control GC T cell responses, thereby implicating intricate controls of GC response by miR-146.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-018-05196-3