Regulation of B-lymphocyte negative and positive selection by tyrosine phosphatase CD45

Abstract

ELIMINATION of self-reactive B cells must be balanced against the need for B-cell diversity for antibody responses to pathogens. To analyse factors that determine the extent of B-cell negative selection, we crossed CD45-deficient mice1 with mice carrying immunoglobulin transgenes specific for hen egg lysozyme (HEL). CD45 positively regulates antigen-receptor signalling2–9 and CD45-deficient HEL-specific B cells gave diminished signalling in response to HEL. Significantly, few mature CD45−/− B cells accumulated, despite normal immature B-cell production. Circulating HEL autoantigen mediates negative selection of mature CD45+/+ HEL-binding B cells10 but, in striking contrast, the autoantigen positively selected CD45−/− HEL-binding B cells, promoting their accumulation as long-lived IgDhi cells. These findings are consistent with a signal-threshold model for B-cell selection and demonstrate that changes in antigen receptor signalling can cause high-affinity self-reactive B cells to be actively retained instead of eliminated, thus revealing a potential mechanism for inherited susceptibility to autoimmune disease.