Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 47, Pages E6515-E6524Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1519925112
Keywords
CD45; CD22; BCR signaling; B-cell development; TCR signaling
Categories
Funding
- Rheumatology Research Foundation
- NIH [K08 AR059723]
- Arthritis National Research Foundation
- National Science Foundation
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The receptor-like tyrosine phosphatase CD45 regulates antigen receptor signaling by dephosphorylating the C-terminal inhibitory tyrosine of the src family kinases. However, despite its abundance, the function of the large, alternatively spliced extracellular domain of CD45 has remained elusive. We used normally spliced CD45 transgenes either incorporating a phosphatase-inactivating point mutation or lacking the cytoplasmic domain to uncouple the enzymatic and noncatalytic functions of CD45 in lymphocytes. Although these transgenes did not alter T-cell signaling or development irrespective of endogenous CD45 expression, both partially rescued the phenotype of CD45-deficient B cells. We identify a noncatalytic role for CD45 in regulating tonic, but not antigen-mediated, B-cell antigen receptor (BCR) signaling through modulation of the function of the inhibitory coreceptor CD22. This finding has important implications for understanding how naive B cells maintain tonic BCR signaling while restraining inappropriate antigen-dependent activation to preserve clonal ignorance.
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