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.
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-2794, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Holst
authors.forename: Haopeng
authors.initials: H
authors.lastname: Wang
authors.forename: Kelly Durick
authors.initials: KD
authors.lastname: Eder
authors.forename: Creg J
authors.initials: CJ
authors.lastname: Workman
authors.forename: Kelli L
authors.initials: KL
authors.lastname: Boyd
authors.forename: Zachary
authors.initials: Z
authors.lastname: Baquet
authors.forename: Harvir
authors.initials: H
authors.lastname: Singh
authors.forename: Karen
authors.initials: K
authors.lastname: Forbes
authors.forename: Andrzej
authors.initials: A
authors.lastname: Chruscinski
authors.forename: Richard
authors.initials: R
authors.lastname: Smeyne
authors.forename: Nicolai S C
authors.initials: NS
authors.lastname: van Oers
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Utz
authors.forename: Dario A A
authors.initials: DA
authors.lastname: Vignali
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000502:physiology*; D017252:CD3 Complex / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism / Q000502:physiology*
chemical_list: D017252:CD3 Complex; D011948:Receptors, Antigen, T-Cell