CTLA-4 disrupts ZAP70 microcluster formation with reduced T cell/APC dwell times and calcium mobilization.
CTLA-4 is a co-receptor that modulates the threshold of T cell activation and autoimmunity. We previously showed that CTLA-4 reverses the TCR-mediated stop signal needed for T cell/APC interactions [Schneider et al., Science 2006, 313: 1972]. In this study, using a different T cell system, we show that CTLA-4 expression changed the behavior of T8.1 T cells by reducing the contact time between T cell and APC, preventing re-inforced contacts, and reducing the contact area at the immunological synapse. This led to a major reduction in Ca(2+) influx/mobilization and interleukin-2 production. Further, anti-CD3/CTLA-4 increased T cell motility on antibody-coated glass slides, concurrent with an abrogation of ZAP70 microcluster formation. Our findings further support a role for CTLA-4 in limiting the interaction between T cell and APC that is needed for optimal activation.
Schneider
Helga
H
Cell Signalling Section, Department of Pathology, University of Cambridge, Cambridge, UK.
Smith
Xin
X
Liu
Hebin
H
Bismuth
Georges
G
Rudd
Christopher E
CE
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000378:metabolism; D015703:Antigens, CD / Q000276:immunology* / Q000378:metabolism; D000943:Antigens, Differentiation / Q000276:immunology* / Q000378:metabolism; D060908:CTLA-4 Antigen; D002118:Calcium / Q000378:metabolism*; D002448:Cell Adhesion / Q000276:immunology; D002450:Cell Communication / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D002118:Calcium