Monophosphorylation of CD79a and CD79b ITAM motifs initiates a SHIP-1 phosphatase-mediated inhibitory signaling cascade required for B cell anergy

Shannon K. O'Neill, Andrew Getahun, Stephen B. Gauld, Kevin T. Merrell, Idan Tamir, Mia J. Smith, Joseph M. Dal Porto, Quan Zhen Li, John C. Cambier

Research output: Contribution to journalArticle

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Abstract

Anergic B cells are characterized by impaired signaling and activation after aggregation of their antigen receptors (BCR). The molecular basis of this impairment is not understood. In studies reported here, Src homology-2 (SH2)-containing inositol 5-phosphatase SHIP-1 and its adaptor Dok-1 were found to be constitutively phosphorylated in anergic B cells, and activation of this inhibitory circuit was dependent on Src-family kinase activity and consequent to biased BCR immunoreceptor tyrosine-based activation motif (ITAM) monophosphorylation. B cell-targeted deletion of SHIP-1 caused severe lupus-like disease. Moreover, absence of SHIP-1 in B cells led to loss of anergy as indicated by restoration of BCR signaling, loss of anergic surface phenotype, and production of autoantibodies. Thus, chronic BCR signals maintain anergy in part via ITAM monophosphorylation-directed activation of an inhibitory signaling circuit involving SHIP-1 and Dok-1.

Original languageEnglish (US)
Pages (from-to)746-756
Number of pages11
JournalImmunity
Volume35
Issue number5
DOIs
Publication statusPublished - Nov 23 2011

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases
  • Immunology

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