Biomedical Sciences (BMS) Graduate Program, University of California San Francisco, San Francisco, United States
James L Mueller
Rosalind Russell and Ephraim P. Engleman Arthritis Research Center, Division of Rheumatology, Department of Medicine, University of California San Francisco, San Francisco, United States
Anne Satterthwaite
Department of Immunology, UT Southwestern Medical Center, Dallas, United States
Lee Ann Garrett-Sinha
Department of Biochemistry, University at Buffalo, The State University of New York, Buffalo, United States
Frank Brombacher
International Center for Genetic Engineering and Biotechnology (ICGEB), Cape Town, South Africa; Institute of Infectious Diseases and Molecular Medicine, Division of Immunology, Faculty of Health Sciences, University of Cape Town & Medical Research Council (SAMRC), Cape Town, South Africa
Rosalind Russell and Ephraim P. Engleman Arthritis Research Center, Division of Rheumatology, Department of Medicine, University of California San Francisco, San Francisco, United States
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.
