B cells drive lymphocyte activation and expansion in mice with the CD45 wedge mutation and Fas deficiency

• Type of Material: Article
• Authors: Vikas Gupta, Emory University; Michelle L. Hermiston, University of California San Francisco; Gail Cassafer, University of California San Francisco; David I. Daikh, University of California San Francisco; Arthur Weiss, University of California San Francisco
• Language: English
• Date: 2008-11-24
• Publisher: Rockefeller University Press
• Publication Version: Final Published Version
• Copyright Statement: © 2008 Gupta et al.
• License: Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1084/jem.20081204
• Title of Journal or Parent Work: Journal of Experimental Medicine
• ISSN: 0022-1007
• Volume: 205
• Issue: 12
• Start Page: 2755
• End Page: 2761
• Grant/Funding Information: This work was supported by the National Institutes of Health (NIH) Medical Scientist Training Program and by NIH PO1 AI35297.
• Keywords: SYSTEMIC-LUPUS-ERYTHEMATOSUS; Immunology; SRC-FAMILY KINASES; Life Sciences & Biomedicine; APOPTOSIS; Research & Experimental Medicine; COMPLEMENT RECEPTORS; Science & Technology; Medicine, Research & Experimental; DISEASE; REGULATORS BIM; INHIBITORY WEDGE; TYROSINE-PHOSPHATASE; AUTOIMMUNITY; T-CELLS
• Research Categories: Health Sciences, Immunology; Engineering, Biomedical; Biology, Microbiology

Abstract

CD45 and Fas regulate tyrosine phosphorylation and apoptotic signaling pathways, respectively. Mutation of an inhibitory wedge motif in CD45 (E613R) results in hyperre- sponsive thymocytes and B cells on the C57BL/6 background, but no overt autoimmunity, whereas Fas deletion results in a mild autoimmune disease on the same genetic background. In this study, we show that these two mutations cooperate in mice, causing early lethality, autoantibody production, and substantial lymphoproliferation. In double-mutant mice, this phenotype was dependent on both T and B cells. T cell activation required signaling in response to endogenous or commensal antigens, demonstrated by the introduction of a transgenic T cell receptor. Genetic deletion of B cells also prevented T cell activation. Similarly, T cells were necessary for B cell autoantibody production. However, B cells appeared to be intrinsically activated even in the absence of T cells, suggesting that they may drive the phenotype of these mice. These results reveal a requirement for careful control of B cell signaling and cell death in preventing inappropriate lymphocyte activation and autoimmunity.