Scalable signaling mediated by T cell antigen receptor-CD3 ITAMs ensures effective negative selection and prevents autoimmunity.
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.
Holst
Jeff
J
Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-2794, USA.
Wang
Haopeng
H
Eder
Kelly Durick
KD
Workman
Creg J
CJ
Boyd
Kelli L
KL
Baquet
Zachary
Z
Singh
Harvir
H
Forbes
Karen
K
Chruscinski
Andrzej
A
Smeyne
Richard
R
van Oers
Nicolai S C
NS
Utz
Paul J
PJ
Vignali
Dario A A
DA
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*
D017252:CD3 Complex; D011948:Receptors, Antigen, T-Cell