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

Jeff Holst1, Haopeng Wang, Kelly Durick Eder

  • 1Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-2794, USA.

Nature Immunology
|May 13, 2008
PubMed

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.

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