CD28 and CTLA-4 coreceptor expression and signal transduction

Immunol Rev. 2009 May;229(1):12-26. doi: 10.1111/j.1600-065X.2009.00770.x.

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.

Publication types

  • Review

MeSH terms

  • 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
  • CD28 Antigens / immunology*
  • CD28 Antigens / metabolism
  • CTLA-4 Antigen
  • Contractile Proteins / immunology
  • Contractile Proteins / metabolism
  • 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
  • Protein-Serine-Threonine Kinases / immunology
  • Protein-Serine-Threonine Kinases / metabolism
  • Signal Transduction / immunology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • CD28 Antigens
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Contractile Proteins
  • Filamins
  • ICOS protein, human
  • Inducible T-Cell Co-Stimulator Protein
  • Microfilament Proteins
  • Phosphatidylinositol 3-Kinases
  • 3-Phosphoinositide-Dependent Protein Kinases
  • Protein-Serine-Threonine Kinases