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- Title
Scalable signaling mediated by T cell antigen receptor–CD3 ITAMs ensures effective negative selection and prevents autoimmunity.
- Authors
Holst, Jeff; Wang, Haopeng; Eder, Kelly Durick; Workman, Creg J; Boyd, Kelli L; Baquet, Zachary; Singh, Harvir; Forbes, Karen; Chruscinski, Andrzej; Smeyne, Richard; van Oers, Nicolai S C; Utz, Paul J; Vignali, Dario A A
- 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.
- Publication
Nature Immunology, 2008, Vol 9, Issue 6, p658
- ISSN
1529-2908
- Publication type
Article
- DOI
10.1038/ni.1611