title: Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4.
abstract: Cytotoxic T lymphocyte antigen 4 (CTLA-4) is an essential negative regulator of T cell immune responses whose mechanism of action is the subject of debate. CTLA-4 shares two ligands (CD80 and CD86) with a stimulatory receptor, CD28. Here, we show that CTLA-4 can capture its ligands from opposing cells by a process of trans-endocytosis. After removal, these costimulatory ligands are degraded inside CTLA-4-expressing cells, resulting in impaired costimulation via CD28. Acquisition of CD86 from antigen-presenting cells is stimulated by T cell receptor engagement and observed in vitro and in vivo. These data reveal a mechanism of immune regulation in which CTLA-4 acts as an effector molecule to inhibit CD28 costimulation by the cell-extrinsic depletion of ligands, accounting for many of the known features of the CD28-CTLA-4 system.
authors.affiliation: Medical Research Council (MRC) Centre for Immune Regulation, School of Immunity and Infection, Institute of Biomedical Research, University of Birmingham Medical School, Birmingham B15 2TT, UK.
authors.forename: Omar S
authors.initials: OS
authors.lastname: Qureshi
authors.forename: Yong
authors.initials: Y
authors.lastname: Zheng
authors.forename: Kyoko
authors.initials: K
authors.lastname: Nakamura
authors.forename: Kesley
authors.initials: K
authors.lastname: Attridge
authors.forename: Claire
authors.initials: C
authors.lastname: Manzotti
authors.forename: Emily M
authors.initials: EM
authors.lastname: Schmidt
authors.forename: Jennifer
authors.initials: J
authors.lastname: Baker
authors.forename: Louisa E
authors.initials: LE
authors.lastname: Jeffery
authors.forename: Satdip
authors.initials: S
authors.lastname: Kaur
authors.forename: Zoe
authors.initials: Z
authors.lastname: Briggs
authors.forename: Tie Z
authors.initials: TZ
authors.lastname: Hou
authors.forename: Clare E
authors.initials: CE
authors.lastname: Futter
authors.forename: Graham
authors.initials: G
authors.lastname: Anderson
authors.forename: Lucy S K
authors.initials: LS
authors.lastname: Walker
authors.forename: David M
authors.initials: DM
authors.lastname: Sansom
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology* / Q000378:metabolism; D018122:B7-1 Antigen / Q000276:immunology* / Q000378:metabolism; D051940:B7-2 Antigen / Q000276:immunology* / Q000378:metabolism; D018106:CD28 Antigens / Q000276:immunology*; D016466:CHO Cells; D060908:CTLA-4 Antigen; D006224:Cricetinae; D003412:Cricetulus; D003713:Dendritic Cells / Q000276:immunology; D004705:Endocytosis; D006801:Humans; D019169:Jurkat Cells; D008024:Ligands; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D010047:Ovalbumin / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D008024:Ligands; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D010047:Ovalbumin