CD28 and CTLA-4 coreceptor expression and signal transduction.
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.
Department of Pathology, Cell Signalling Section, University of Cambridge, Cambridge, UK. cer51@cam.ac.uk
Christopher E
CE
Rudd
Alison
A
Taylor
Helga
H
Schneider
D064413:3-Phosphoinositide-Dependent Protein Kinases; D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000276:immunology* / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D018106:CD28 Antigens / Q000276:immunology* / Q000378:metabolism; D060908:CTLA-4 Antigen; D003285:Contractile Proteins / Q000276:immunology / Q000378:metabolism; D064448:Filamins; D006801:Humans; D060889:Inducible T-Cell Co-Stimulator Protein; D008213:Lymphocyte Activation / Q000276:immunology*; D008840:Microfilament Proteins / Q000276:immunology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D064413:3-Phosphoinositide-Dependent Protein Kinases; D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; D003285:Contractile Proteins; D064448:Filamins; D060889:Inducible T-Cell Co-Stimulator Protein; D008840:Microfilament Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; C556706:CTLA4 protein, human; C556692:ICOS protein, human