title: Confusing signals: recent progress in CTLA-4 biology.
abstract: The mechanism of action of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) remains surprisingly unclear. Regulatory T (Treg) cells can use CTLA-4 to elicit suppression; however, CTLA-4 also operates in conventional T cells, reputedly by triggering inhibitory signals. Recently, interactions mediated via the CTLA-4 cytoplasmic domain have been shown to preferentially affect Treg cells, yet other evidence suggests that the extracellular domain of CTLA-4 is sufficient to elicit suppression. Here, we discuss these paradoxical findings in the context of CTLA-4-mediated ligand regulation. We propose that the function of CTLA-4 cytoplasmic domain is not to transmit inhibitory signals but to precisely control the turnover, cellular location, and membrane delivery of CTLA-4 to facilitate its central function: regulating the access of CD28 to their shared ligands.
authors.affiliation: Institute for Immunity & Transplantation, University College London Division of Infection & Immunity, Royal Free Campus, London, NW3 2PF, UK. Electronic address: lucy.walker@ucl.ac.uk.
authors.forename: Lucy S K
authors.initials: LS
authors.lastname: Walker
authors.affiliation: Institute for Immunity & Transplantation, University College London Division of Infection & Immunity, Royal Free Campus, London, NW3 2PF, UK. Electronic address: d.sansom@ucl.ac.uk.
authors.forename: David M
authors.initials: DM
authors.lastname: Sansom
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D002465:Cell Movement / Q000235:genetics; D015536:Down-Regulation; D006801:Humans; D008024:Ligands; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D021381:Protein Transport; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism
chemical_list: D060908:CTLA-4 Antigen; D008024:Ligands
keywords: CD28; CTLA-4; T cell activation; T cell tolerance; costimulation