Abstract
T-cell activation is mediated by antigen-specific signals from the TCRzeta/CD3 and CD4-CD8-p56lck complexes in combination with additional co-signals provided by coreceptors such as CD28, inducible costimulator (ICOS), cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death (PD-1), and others. CD28 and ICOS provide positive signals that promote and sustain T-cell responses, while CTLA-4 and PD-1 limit responses. The balance between stimulatory and inhibitory co-signals determines the ultimate nature of T-cell responses where response to foreign pathogen is achieved without excess inflammation and autoimmunity. In this review, we outline the current knowledge of the CD28 and CTLA-4 signaling mechanisms [involving phosphatidylinositol 3 kinase (PI3K), growth factor receptor-bound protein 2 (Grb2), Filamin A, protein kinase C theta (PKCtheta), and phosphatases] that control T-cell immunity. We also present recent findings on T-cell receptor-interacting molecule (TRIM) regulation of CTLA-4 surface expression, and a signaling pathway involving CTLA-4 activation of PI3K and protein kinase B (PKB)/AKT by which cell survival is ensured under conditions of anergy induction.
MeSH terms
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3-Phosphoinositide-Dependent Protein Kinases
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Adaptor Proteins, Signal Transducing / immunology
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Antigens, CD / immunology*
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Antigens, CD / metabolism
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Antigens, Differentiation, T-Lymphocyte / immunology
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Antigens, Differentiation, T-Lymphocyte / metabolism
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CD28 Antigens / immunology*
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CD28 Antigens / metabolism
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CTLA-4 Antigen
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Contractile Proteins / immunology
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Contractile Proteins / metabolism
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Filamins
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Humans
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Inducible T-Cell Co-Stimulator Protein
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Lymphocyte Activation / immunology*
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Microfilament Proteins / immunology
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Microfilament Proteins / metabolism
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Phosphatidylinositol 3-Kinases / immunology
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Phosphatidylinositol 3-Kinases / metabolism
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Protein Serine-Threonine Kinases / immunology
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Protein Serine-Threonine Kinases / metabolism
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Signal Transduction / immunology
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T-Lymphocytes / immunology*
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T-Lymphocytes / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Antigens, CD
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Antigens, Differentiation, T-Lymphocyte
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CD28 Antigens
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CTLA-4 Antigen
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CTLA4 protein, human
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Contractile Proteins
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Filamins
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ICOS protein, human
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Inducible T-Cell Co-Stimulator Protein
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Microfilament Proteins
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3-Phosphoinositide-Dependent Protein Kinases
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Protein Serine-Threonine Kinases