Journal
NATURE IMMUNOLOGY
Volume 9, Issue 6, Pages 658-666Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ni.1611
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Funding
- NCI NIH HHS [CA-21765] Funding Source: Medline
- NHLBI NIH HHS [N0I-HV-28183] Funding Source: Medline
- NIAID NIH HHS [R56 AI052199, AI-52199] Funding Source: Medline
- NIDDK NIH HHS [U19-DK-6134] Funding Source: Medline
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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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