The juxtamembrane wedge negatively regulates CD45 function in B cells.
CD45 is a receptor-like protein tyrosine phosphatase highly expressed on all nucleated hematopoietic cells. We previously generated mice containing a point mutation in the juxtamembrane wedge of CD45. Demonstrating the critical negative regulatory function of the wedge, the CD45 E613R mutation led to a lymphoproliferative disorder (LPD) and a lupus-like autoimmune syndrome. Here we show the central role of B cells in this phenotype. Genetic elimination of B cells, but not T cells, ablates the LPD. In contrast to CD45-deficient B cells, the E613R mutation generates hyperresponsive B cells. Comparison of CD45-deficient and CD45 E613R mice reveals dichotomous effects of these mutations on B cell development. Together, the results support a role for CD45 as a rheostat, with both positive and negative regulatory functions, that fine-tunes the signal transduction threshold at multiple checkpoints in B cell development.
Hermiston
Michelle L
ML
Department of Pediatrics, University of California, San Francisco, San Francisco, California 94143, USA.
Tan
Allison L
AL
Gupta
Vikas A
VA
Majeti
Ravindra
R
Weiss
Arthur
A
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D015153:Blotting, Western; D019281:Dimerization; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D047468:Immunoprecipitation; D017493:Leukocyte Common Antigens / Q000235:genetics* / Q000378:metabolism*; D008232:Lymphoproliferative Disorders / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D020125:Mutation, Missense / Q000235:genetics; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000276:immunology*
D017493:Leukocyte Common Antigens