CD28 and CTLA-4 coreceptor expression and signal transduction

• Published in: Immunological reviews 2009-05, Vol.229 (1), p.12-26
• Main Authors: Rudd, Christopher E, Taylor, Alison, Schneider, Helga
• Format: Article
• Language: English
• Subjects: 3-Phosphoinositide-Dependent Protein Kinases; Adaptor Proteins, Signal Transducing - immunology; Adaptor Proteins, Signal Transducing - metabolism; Animals; Antigens, CD - immunology; Antigens, CD - metabolism; Antigens, Differentiation, T-Lymphocyte - immunology; Antigens, Differentiation, T-Lymphocyte - metabolism; apoptosis; CD28; CD28 Antigens - immunology; CD28 Antigens - metabolism; Contractile Proteins - immunology; Contractile Proteins - metabolism; CTLA-4; CTLA-4 Antigen; Filamins; Humans; Inducible T-Cell Co-Stimulator Protein; Lymphocyte Activation - immunology; Microfilament Proteins - immunology; Microfilament Proteins - metabolism; Phosphatidylinositol 3-Kinases - immunology; Phosphatidylinositol 3-Kinases - metabolism; PKB/AKT; Protein Serine-Threonine Kinases - immunology; Protein Serine-Threonine Kinases - metabolism; Signal Transduction - immunology; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; TRIM
• ISSN: 0105-2896; 1600-065X
• DOI: 10.1111/j.1600-065X.2009.00770.x

T-cell activation is mediated by antigen-specific signals from the TCRζ/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 θ (PKCθ), 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.