@article{e260dd58ffbb49e3ad1fd84236ab481d,
title = "Scalable signaling mediated by T cell antigen receptor-CD3 ITAMs ensures effective negative selection and prevents autoimmunity",
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.",
author = "Jeff Holst and Haopeng Wang and Eder, {Kelly Durick} and Workman, {Creg J.} and Boyd, {Kelli L.} and Zachary Baquet and Harvir Singh and Karen Forbes and Andrzej Chruscinski and Richard Smeyne and {van Oers}, {Nicolai S C} and Utz, {Paul J.} and Vignali, {Dario A A}",
note = "Funding Information: We thank D. Green, M. Davis and J. Ihle for reviewing the manuscript; L. Collison (St. Jude Children{\textquoteright}s Research Hospital) for mice with inflammatory bowel disease; C. Terhorst (Harvard Medical School) for Cd3eDP/DP mice; N. van Oers (University of Texas Southwestern Medical Center) for CD3z-KO Tg1-6M mice; M. Davis for 3A9 TCR–transgenic mice; K. Vignali, Y. Wang, S. Dilioglou, A. Burton and E. Vincent for technical assistance; the Vignali lab for assistance with bone marrow collection; R. Cross, J. Hoffrage, J. Smith and Y. He for flow cytometry; S. Rowe, J. Gatewood and J. Smith for cytokine analysis; L. Zhang of the Cell and Tissue Imaging facility for image acquisition; the staff of the Flow Cytometry and Cell Sorting Shared Resource facility for purification by magnetic-activated cell sorting; and the Hartwell Center for DNA sequencing. Supported by the National Institutes of Health (AI-52199; and U19-DK-6134 to P.J.U.), the St. Jude National Cancer Institute Cancer Center (CA-21765) and the American Lebanese Syrian Associated Charities (D.A.A.V.) the National Heart, Lung and Blood Institute (proteomics contract NOI-HV-28183 to P.J.U.); and the Floren Family Trust (P.J.U.).",
year = "2008",
month = jun,
doi = "10.1038/ni.1611",
language = "English (US)",
volume = "9",
pages = "658--666",
journal = "Nature immunology",
issn = "1529-2908",
publisher = "Nature Publishing Group",
number = "6",
}