Article abstract
Nature Immunology 9, 658 - 666 (2008)
Published online: 11 May 2008 | doi:10.1038/ni.1611
Scalable signaling mediated by T cell antigen receptor–CD3 ITAMs ensures effective negative selection and prevents autoimmunity
Jeff Holst1,8, Haopeng Wang1,4,9, Kelly Durick Eder1,9, Creg J Workman1,9, Kelli L Boyd2, Zachary Baquet3, Harvir Singh6, Karen Forbes1, Andrzej Chruscinski6, Richard Smeyne3, Nicolai S C van Oers7, Paul J Utz6 & Dario A A Vignali1,5
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.
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-2794, USA.
- Animal Resource Center, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-2794, USA.
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-2794, USA.
- Interdisciplinary Program, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
- Department of Pathology, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
- Division of Immunology & Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
- Department of Immunology and Department of Microbiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9093, USA.
- Present address: Gene & Stem Cell Therapy Program, Centenary Institute of Cancer Medicine & Cell Biology, University of Sydney, NSW 2042, Australia.
- These authors contributed equally to this work.
Correspondence to: Dario A A Vignali1,5 e-mail: Dario.vignali@stjude.org
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