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

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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.

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Author notes

  1. Jason G. Cyster

    Present address: Department of Microbiology and Immunology, University of California, San Francisco, California, 94143-0414, USA

Authors and Affiliations

  1. Department of Microbiology and Immunology, Program in Immunology and Howard Hughes Medical Institute, Beckman Center, Stanford University School of Medicine, Stanford, California, 94305, USA

    Jason G. Cyster, James I. Healy & Christopher C. Goodnow

  2. Department of Immunology, Medical Research Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812, Japan

    Kenji Kishihara

  3. The Amgen Institute and Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario, Canada, M4X 1K9

    Tak W. Mak

  4. Howard Hughes Medical Institute, Department of Pathology, Washington University School of Medicine, St Louis, Missouri, 63110, USA

    Matthew L. Thomas

Authors
  1. Jason G. Cyster
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  2. James I. Healy
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  3. Kenji Kishihara
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  4. Tak W. Mak
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  5. Matthew L. Thomas
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  6. Christopher C. Goodnow
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Cyster, J., Healy, J., Kishihara, K. et al. Regulation of B-lymphocyte negative and positive selection by tyrosine phosphatase CD45. Nature 381, 325–328 (1996). https://doi.org/10.1038/381325a0

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  • DOI: https://doi.org/10.1038/381325a0

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