Scalable signaling mediated by T cell antigen receptor-CD3 ITAMs ensures effective negative selection and prevents autoimmunity

Jeff Holst, Haopeng Wang, Kelly Durick Eder, Creg J. Workman, Kelli L. Boyd, Zachary Baquet, Harvir Singh, Karen Forbes, Andrzej Chruscinski, Richard Smeyne, Nicolai S C van Oers, Paul J. Utz, Dario A A Vignali

Research output: Contribution to journalArticlepeer-review

103 Scopus citations

Abstract

The T cell antigen receptor (TCR)-CD3 complex is unique in having ten cytoplasmic immunoreceptor tyrosine-based activation motifs (ITAMs). The physiological importance of this high TCR ITAM number is unclear. Here we generated 25 groups of mice expressing various combinations of wild-type and mutant ITAMs in TCR-CD3 complexes. Mice with fewer than seven wild-type CD3 ITAMs developed a lethal, multiorgan autoimmune disease caused by a breakdown in central rather than peripheral tolerance. Although there was a linear correlation between the number of wild-type CD3 ITAMs and T cell proliferation, cytokine production was unaffected by ITAM number. Thus, high ITAM number provides scalable signaling that can modulate proliferation yet ensure effective negative selection and prevention of autoimmunity.

Original languageEnglish (US)
Pages (from-to)658-666
Number of pages9
JournalNature Immunology
Volume9
Issue number6
DOIs
StatePublished - Jun 1 2008

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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