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

Brian T. Fife, Jeffrey A. Bluestone

Research output: Contribution to journalArticlepeer-review

503 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)166-182
Number of pages17
JournalImmunological Reviews
Volume224
Issue number1
DOIs
StatePublished - Aug 2008

Keywords

  • Autoimmunity
  • CTLA-4
  • PD-1
  • PD-L1
  • Regulation
  • Tolerance

Fingerprint

Dive into the research topics of 'Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways'. Together they form a unique fingerprint.

Cite this