title: 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 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.
authors.affiliation: Department of Medicine, Biomedical Sciences Graduate Program, Medical Scientist Training Program, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Vikas A
authors.initials: VA
authors.lastname: Gupta
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Hermiston
authors.forename: Gail
authors.initials: G
authors.lastname: Cassafer
authors.forename: David I
authors.initials: DI
authors.lastname: Daikh
authors.forename: Arthur
authors.initials: A
authors.lastname: Weiss
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D049109:Cell Proliferation; D017493:Leukocyte Common Antigens / Q000235:genetics* / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009929:Organ Size; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013154:Spleen / Q000033:anatomy & histology / Q000276:immunology; D015996:Survival Rate; D019014:fas Receptor / Q000235:genetics* / Q000276:immunology
chemical_list: D001323:Autoantibodies; D011948:Receptors, Antigen, T-Cell; D019014:fas Receptor; D017493:Leukocyte Common Antigens