Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, CD / immunology
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Antigens, CD / metabolism*
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Antigens, CD / physiology
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Antigens, Differentiation / immunology
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Antigens, Differentiation / metabolism*
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Antigens, Differentiation / physiology
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CD3 Complex / immunology
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CTLA-4 Antigen
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Cell Movement / immunology*
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Cells, Cultured
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Humans
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Immune Sera / physiology
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Intracellular Signaling Peptides and Proteins / metabolism
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Intracellular Signaling Peptides and Proteins / physiology*
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Mice
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Myosin-Light-Chain Kinase / physiology*
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Phosphatidylinositol 3-Kinases / physiology*
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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Proto-Oncogene Proteins c-vav / physiology*
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Pseudopodia / immunology
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T-Lymphocytes / cytology*
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T-Lymphocytes / enzymology
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
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T-Lymphocytes, Cytotoxic / cytology
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T-Lymphocytes, Cytotoxic / enzymology
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T-Lymphocytes, Cytotoxic / immunology
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T-Lymphocytes, Cytotoxic / metabolism
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Up-Regulation / immunology
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cdc42 GTP-Binding Protein / physiology*
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rho-Associated Kinases
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rhoA GTP-Binding Protein / metabolism
Substances
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Antigens, CD
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Antigens, Differentiation
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CD3 Complex
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CTLA-4 Antigen
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CTLA4 protein, human
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Ctla4 protein, mouse
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Immune Sera
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Intracellular Signaling Peptides and Proteins
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Proto-Oncogene Proteins c-vav
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Vav1 protein, mouse
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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rho-Associated Kinases
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Myosin-Light-Chain Kinase
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cdc42 GTP-Binding Protein
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rhoA GTP-Binding Protein