Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways

Immunol Rev. 2008 Aug:224:166-82. doi: 10.1111/j.1600-065X.2008.00662.x.

Abstract

Classically, the CD28/cytotoxic T-lymphocyte antigen-4 (CTLA-4) and B7 families of cell surface molecules regulate complex signaling pathways that profoundly affect T-cell responses. The recent identification and characterization of additional CD28 and B7 family members including programmed death-1 (PD-1), programmed death ligand-1 (PD-L1) (B7-H1), and PD-L2 (B7-DC) has added to the complexity and greater appreciation of how surface molecules control T-cell activation and peripheral tolerance. CD28/B7 interactions mediate co-stimulation and significantly enhance peripheral T-cell responses. CTLA-4, in contrast, interacting with the same B7 molecules, results in decreased T-lymphocyte activity and regulates the immune response. Similarly, PD-1 interactions with PD-L1 and PD-L2 downmodulate T-cell immune responses. Despite these similarities, the regulatory roles of the CTLA-4 and PD-1 pathways are distinct. This may be due, at least in part, to the differential expression patterns of the CTLA-4 and PD-1 ligands both temporally and spatially. This article examines the role of CTLA-4 and PD-1 in limiting autoreactivity and establishing peripheral self-tolerance with the hypothesis that CTLA-4 signals are required early in the lymph node during initiation of an immune response and PD-1 pathways act late at the tissue sites to limit T-cell activity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Abatacept
  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / therapeutic use
  • Antigens, CD / immunology*
  • Antigens, CD / metabolism
  • Apoptosis Regulatory Proteins / immunology*
  • Apoptosis Regulatory Proteins / metabolism
  • Autoimmune Diseases / immunology*
  • Autoimmune Diseases / therapy
  • Autoimmunity
  • CTLA-4 Antigen
  • Clonal Anergy / immunology
  • Humans
  • Immune Tolerance / immunology*
  • Immunoconjugates / immunology*
  • Immunotherapy
  • Lymphocyte Activation / immunology
  • Programmed Cell Death 1 Receptor
  • Signal Transduction / immunology
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism

Substances

  • Antibodies, Monoclonal
  • Antigens, CD
  • Apoptosis Regulatory Proteins
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Immunoconjugates
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Abatacept