IgM and IgD B cell receptors differentially respond to endogenous antigens and control B cell fate

Abstract
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Abstract

Naive B cells co-express two BCR isotypes, IgM and IgD, with identical antigen-binding domains but distinct constant regions. IgM but not IgD is downregulated on autoreactive B cells. Because these isotypes are presumed to be redundant, it is unknown how this could impose tolerance. We introduced the Nur77-eGFP reporter of BCR signaling into mice that express each BCR isotype alone. Despite signaling strongly in vitro, IgD is less sensitive than IgM to endogenous antigen in vivo and developmental fate decisions are skewed accordingly. IgD-only Lyn^-/- B cells cannot generate autoantibodies and short-lived plasma cells (SLPCs) in vivo, a fate thought to be driven by intense BCR signaling induced by endogenous antigens. Similarly, IgD-only B cells generate normal germinal center, but impaired IgG1⁺ SLPC responses to T-dependent immunization. We propose a role for IgD in maintaining the quiescence of autoreactive B cells and restricting their differentiation into autoantibody secreting cells.

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Author details

Mark Noviski

Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-8072-1059
James L Mueller

Department of Medicine, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Anne Satterthwaite

Department of Immunology, UT Southwestern Medical Center, Dallas, United States

Competing interests
The authors declare that no competing interests exist.
Lee Ann Garrett-Sinha

Department of Biochemistry, University at Buffalo, The State University of New York, Buffalo, United States

Competing interests
The authors declare that no competing interests exist.
Frank Brombacher

International Center for Genetic Engineering and Biotechnology (ICGE), Cape Town, Cape Town, South Africa

Competing interests
The authors declare that no competing interests exist.
Julie Zikherman

Department of Medicine, University of California, San Francisco, San Francisco, United States

For correspondence
julie.zikherman@ucsf.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-0873-192X

Funding

National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 A127648)

Julie Zikherman

National Science Foundation (1650113)

Mark Noviski

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols of the University of California, San Francisco. The protocol was approved by the IACUC committee of the University of California, San Francisco (Protocol number: AN171020-01).

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.