title: Intracellular trafficking of CTLA-4 and focal localization towards sites of TCR engagement.
abstract: T lymphocyte receptor CTLA-4 binds costimulatory molecules CD80 (B7-1) and CD86 (B7-2) with high avidity and negatively regulates T cell activation. CTLA-4 functions at the cell surface, yet is primarily localized in intracellular vesicles. Here, we demonstrate cycling of CTLA-4 between intracellular stores and the cell surface. Intracellular vesicles containing CTLA-4 overlapped with endocytic compartment(s) and with perforin-containing secretory granules. Cell surface expression of CTLA-4 was rapidly increased by raising intracellular calcium levels. During T cell activation, intracellular and cell surface CTLA-4 became focused towards sites of TCR activation. Cycling and directional control of CTLA-4 expression may regulate its functional interaction with APCs bearing peptide-MHC complexes of appropriate specificity and avidity.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, Washington 98121, USA.
authors.forename: P S
authors.initials: PS
authors.lastname: Linsley
authors.forename: J
authors.initials: J
authors.lastname: Bradshaw
authors.forename: J
authors.initials: J
authors.lastname: Greene
authors.forename: R
authors.initials: R
authors.lastname: Peach
authors.forename: K L
authors.initials: KL
authors.lastname: Bennett
authors.forename: R S
authors.initials: RS
authors.lastname: Mittler
mesh_terms: D000069594:Abatacept; D015703:Antigens, CD / Q000378:metabolism*; D000943:Antigens, Differentiation / Q000378:metabolism*; D018122:B7-1 Antigen / Q000378:metabolism*; D051940:B7-2 Antigen; D001692:Biological Transport / Q000276:immunology; D060908:CTLA-4 Antigen; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D016764:Cell Polarity / Q000276:immunology; D002478:Cells, Cultured; D011992:Endosomes / Q000276:immunology / Q000378:metabolism; D006801:Humans; D018796:Immunoconjugates; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015854:Up-Regulation / Q000276:immunology
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497964:CD86 protein, human; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018796:Immunoconjugates; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D011948:Receptors, Antigen, T-Cell; D054353:Perforin; D000069594:Abatacept