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Abstract
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.
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1 Division of Biological Sciences, University of California, La Jolla, San Diego, CA, USA
2 Laboratory Animal Center, College of Medicine, National Taiwan University, Taipei, Taiwan
3 Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA; Department of Medicine, College of Medicine, Seoul National University, Seoul, Korea
4 Department of Laboratory Medicine, China Medical University Hospital, China Medical University, Taichung, Taiwan
5 Toyota Technological Institute, Chicago, IL, USA
6 Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan
7 Howard Hughes Medical Institute and Immunology Program, Ludwig Center at Memorial Sloan-Kettering Cancer Center, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
8 Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA; Division of Infectious Diseases, Department of Medicine, University of California, La Jolla, San Diego, CA, USA
9 Division of Biological Sciences, University of California, La Jolla, San Diego, CA, USA; Moores Cancer Center, University of California, La Jolla, San Diego, CA, USA; Center for Microbiome Innovation, University of California, La Jolla, San Diego, CA, USA