title: CD28-CD80 interactions control regulatory T cell motility and immunological synapse formation.
abstract: Regulatory T cells (Tregs) are essential for tolerance to self and environmental Ags, acting in part by downmodulating costimulatory molecules on the surface of dendritic cells (DCs) and altering naive CD4 T cell-DC interactions. In this study, we show that Tregs form stable conjugates with DCs before, but not after, they decrease surface expression of the costimulatory molecule CD80 on the DCs. We use supported planar bilayers to show that Tregs dramatically slow down but maintain a highly polarized and motile phenotype after recognizing Ag in the absence of costimulation. These motile cells are characterized by distinct accumulations of LFA-1-ICAM-1 in the lamella and TCR-MHC in the uropod, consistent with a motile immunological synapse or "kinapse." However, in the presence of high, but not low, concentrations of CD80, Tregs form stationary, symmetrical synapses. Using blocking Abs, we show that, whereas CTLA-4 is required for CD80 downmodulation, CD28-CD80 interactions are critical for modulating Treg motility in the presence of Ag. Taken together, these results support the hypothesis that Tregs are tuned to alter their motility depending on costimulatory signals.
authors.affiliation: Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR 97239; parkerd@ohsu.edu thauland@stanford.edu.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Thauland
authors.affiliation: Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR 97239;
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Koguchi
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY 10016; and Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7FY, United Kingdom.
authors.forename: Michael L
authors.identifier: http://orcid.org/0000-0003-4983-6389
authors.initials: ML
authors.lastname: Dustin
authors.affiliation: Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR 97239; parkerd@ohsu.edu thauland@stanford.edu.
authors.forename: David C
authors.identifier: http://orcid.org/0000-0003-4456-2788
authors.initials: DC
authors.lastname: Parker
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D000941:Antigens / Q000276:immunology; D018122:B7-1 Antigen / Q000378:metabolism*; D018106:CD28 Antigens / Q000378:metabolism*; D002450:Cell Communication / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D054992:Immunological Synapses / Q000276:immunology* / Q000378:metabolism*; D056747:Immunomodulation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011485:Protein Binding; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*
chemical_list: D000941:Antigens; D018122:B7-1 Antigen; D018106:CD28 Antigens