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Author Notes:
Arthur Weiss: aweiss@medicine.ucsf.edu
We thank A. Roque for his tireless assistance with animal husbandry, T. Defranco, M. Krummel, and A. Abbas for critically reviewing the manuscript, and the Weiss laboratory for helpful comments and suggestions.
The authors have no conflicting financial interests.
Subjects:
Research Funding:
This work was supported by the National Institutes of Health (NIH) Medical Scientist Training Program and by NIH PO1 AI35297.
Keywords:
- Science & Technology
- Life Sciences & Biomedicine
- Immunology
- Medicine, Research & Experimental
- Research & Experimental Medicine
- SYSTEMIC-LUPUS-ERYTHEMATOSUS
- SRC-FAMILY KINASES
- TYROSINE-PHOSPHATASE
- T-CELLS
- COMPLEMENT RECEPTORS
- INHIBITORY WEDGE
- REGULATORS BIM
- AUTOIMMUNITY
- APOPTOSIS
- DISEASE
B cells drive lymphocyte activation and expansion in mice with the CD45 wedge mutation and Fas deficiency
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.
Copyright information:
© 2008 Gupta et al.
This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License (http://creativecommons.org/licenses/by-nc-sa/3.0/).
