The Journal of Experimental Medicine
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Published online November 10, 2008
doi:10.1084/jem.20081204
The Journal of Experimental Medicine, Vol. 205, No. 12, 2755-2761
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Gupta et al.
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BRIEF DEFINITIVE REPORT

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

Vikas A. Gupta2,5,6, Michelle L. Hermiston4, Gail Cassafer1, David I. Daikh1, and Arthur Weiss1,2,3,5,7

1 Division of Rheumatology and the Rosalind Russell Medical Research Center for Arthritis, 2 Department of Medicine, 3 Department of Microbiology and Immunology, 4 Department of Pediatrics, 5 Biomedical Sciences Graduate Program, 6 Medical Scientist Training Program, 7 Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143

CORRESPONDENCE Arthur Weiss: aweiss{at}medicine.ucsf.edu

CD45 and Fas regulate tyrosine phosphorylation and apoptotic signaling pathways, respectively. Mutation of an inhibitory wedge motif in CD45 (E613R) results in hyperresponsive 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.

© 2008 Gupta et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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