CTL-associated antigen-4 ligation induces rapid T cell polarization that depends on phosphatidylinositol 3-kinase, Vav-1, Cdc42, and myosin light chain kinase.
CTLA-4 can negatively regulate cytokine production and proliferation, increase motility, and override the TCR-induced stop-signal needed for stable T cell-APC conjugation. Despite this, little is known regarding whether CTLA-4 can alter T cell morphology and the nature of the signaling events that could account for this event. In this study, we demonstrate that anti-CTLA-4 and CD3/CTLA-4 induce rapid T cell polarization (i.e., within 15-30 min) with increases in lamellipodia, filopodia, and uropod formation. This was observed with anti-CTLA-4 and CD80-Ig ligation of CTLA-4, but not with anti-CD3 alone, or anti-CD3/CD28 coligation. Polarization required PI3K, the guanine nucleotide exchange factor Vav1, the GTP-binding protein Cdc42, as well as myosin L chain kinase. By contrast, a key downstream target of PI3K, protein kinase B, as well as Rho kinase and RhoA, were not needed. Our results demonstrate that CTLA-4 is a potent activator T cell polarization needed for motility, and this process involves specific set of signaling proteins that might contribute to coreceptor regulation of T cell function.
Wei
Bin
B
Molecular Immunology Section, Department of Immunology, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom.
da Rocha Dias
Silvy
S
Wang
Hongyan
H
Rudd
Christopher E
CE
D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D000943:Antigens, Differentiation / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D017252:CD3 Complex / Q000276:immunology; D060908:CTLA-4 Antigen; D002465:Cell Movement / Q000276:immunology*; D002478:Cells, Cultured; D006801:Humans; D007106:Immune Sera / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D009219:Myosin-Light-Chain Kinase / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav / Q000502:physiology*; D011554:Pseudopodia / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology* / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology; D020764:cdc42 GTP-Binding Protein / Q000502:physiology*; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D015703:Antigens, CD; D000943:Antigens, Differentiation; D017252:CD3 Complex; D060908:CTLA-4 Antigen; D007106:Immune Sera; D047908:Intracellular Signaling Peptides and Proteins; D009219:Myosin-Light-Chain Kinase; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D051567:Proto-Oncogene Proteins c-vav; D020764:cdc42 GTP-Binding Protein; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; C496619:Vav1 protein, mouse