Regulation of B-lymphocyte negative and positive selection by tyrosine phosphatase CD45.
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 mice with mice carrying immunoglobulin transgenes specific for hen egg lysozyme (HEL). CD45 positively regulates antigen-receptor signalling 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 cells but, in striking contrast, the autoantigen positively selected CD45-/- HEL-binding B cells, promoting their accumulation as long-lived IgD(hi) 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.
Cyster
J G
JG
Department of Microbiology and Immunology, Program in Immunology, Stanford University School of Medicine, California 94305, USA.
Healy
J I
JI
Kishihara
K
K
Mak
T W
TW
Thomas
M L
ML
Goodnow
C C
CC
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology; D002454:Cell Differentiation / Q000502:physiology*; D002678:Chimera; D002999:Clone Cells; D003433:Crosses, Genetic; D006411:Hematopoiesis, Extramedullary; D017493:Leukocyte Common Antigens / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009113:Muramidase / Q000235:genetics; D015398:Signal Transduction
D017493:Leukocyte Common Antigens; D009113:Muramidase