title: Quantitative differences in CD45 expression unmask functions for CD45 in B-cell development, tolerance, and survival.
abstract: The receptor-like tyrosine phosphatase CD45 positively regulates antigen receptor signaling by dephosphorylating the inhibitory tyrosine of the src family kinases. CD45-deficient mice fail to fully unmask the role of CD45 in B cells because of the expression of a partially redundant tyrosine phosphatase, CD148. However, mice that are doubly deficient in CD45 and CD148 exhibit a very early block in B-cell development, thereby obscuring later roles for CD45. To overcome these limitations, here we take advantage of an allelic series of mice in which CD45 expression is titrated broadly (0-180%). Although high expression of CD45 inhibits T-cell receptor (TCR) signaling, we show that CD45 plays a purely positive regulatory role during B-cell receptor (BCR) signaling. In concert with exaggerated BCR signaling, increasing CD45 expression drives enhanced receptor editing in the bone marrow and profound loss of follicular and marginal zone B cells in the spleen. In the context of the IgHEL/sHEL model of B-cell tolerance, such high CD45 expression transforms anergy into deletion. Unexpectedly, elimination of the autoantigen sHEL in this model system in order to block clonal deletion fails to rescue survival of mature B cells. Rather, high CD45 expression reduces B-cell activating factor receptor (BAFFR) expression and inhibits B-cell activating factor (BAFF)-induced B-cell survival in a cell-intrinsic manner. Taken together, our findings reveal how CD45 function diverges in T cells and B cells, as well as how autoreactive B cells are censored as they transit development.
authors.affiliation: Division of Rheumatology, Department of Medicine, Rosalind Russell Medical Research Center for Arthritis and Howard Hughes Medical Institute, University of California, San Francisco, CA 94143, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Zikherman
authors.forename: Kristin
authors.initials: K
authors.lastname: Doan
authors.forename: Ramya
authors.initials: R
authors.lastname: Parameswaran
authors.forename: William
authors.initials: W
authors.lastname: Raschke
authors.forename: Arthur
authors.initials: A
authors.lastname: Weiss
mesh_terms: D000818:Animals; D053264:B-Cell Activating Factor / Q000378:metabolism; D053265:B-Cell Activation Factor Receptor / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology* / Q000201:enzymology / Q000276:immunology*; D019070:Cell Lineage / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D017635:Clonal Anergy / Q000276:immunology; D017637:Clonal Deletion / Q000276:immunology; D015536:Down-Regulation / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D017493:Leukocyte Common Antigens / Q000276:immunology*; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010766:Phosphorylation; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D008024:Ligands; D011947:Receptors, Antigen, B-Cell; D011948:Receptors, Antigen, T-Cell; C505720:Tnfsf13b protein, mouse; D019061:src-Family Kinases; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse