B cells drive lymphocyte activation and expansion in mice with the CD45 wedge mutation and Fas deficiency.
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.
Gupta
Vikas A
VA
Department of Medicine, Biomedical Sciences Graduate Program, Medical Scientist Training Program, University of California San Francisco, San Francisco, CA 94143, USA.
Hermiston
Michelle L
ML
Cassafer
Gail
G
Daikh
David I
DI
Weiss
Arthur
A
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
D001323:Autoantibodies; D011948:Receptors, Antigen, T-Cell; D019014:fas Receptor; D017493:Leukocyte Common Antigens