Reversal of the TCR stop signal by CTLA-4.
The coreceptor cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is pivotal in regulating the threshold of signals during T cell activation, although the underlying mechanism is still not fully understood. Using in vitro migration assays and in vivo two-photon laser scanning microscopy, we showed that CTLA-4 increases T cell motility and overrides the T cell receptor (TCR)-induced stop signal required for stable conjugate formation between T cells and antigen-presenting cells. This event led to reduced contact periods between T cells and antigen-presenting cells that in turn decreased cytokine production and proliferation. These results suggest a fundamentally different model of reverse stop signaling, by which CTLA-4 modulates the threshold for T cell activation and protects against autoimmunity.
Schneider
Helga
H
Cell Signalling Section, Division of Immunology, Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK.
Downey
Jos
J
Smith
Andrew
A
Zinselmeyer
Bernd H
BH
Rush
Catherine
C
Brewer
James M
JM
Wei
Bin
B
Hogg
Nancy
N
Garside
Paul
P
Rudd
Christopher E
CE
D000818:Animals; D017951:Antigen Presentation; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics / Q000502:physiology*; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology; D060908:CTLA-4 Antigen; D002448:Cell Adhesion; D002465:Cell Movement; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1; D008198:Lymph Nodes / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology*; D014162:Transfection
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D011948:Receptors, Antigen, T-Cell; D018799:Intercellular Adhesion Molecule-1