title: CD152 (CTLA-4) determines CD4 T cell migration in vitro and in vivo.
abstract: BACKGROUND
  Migration of antigen-experienced T cells to secondary lymphoid organs and the site of antigenic-challenge is a mandatory prerequisite for the precise functioning of adaptive immune responses. The surface molecule CD152 (CTLA-4) is mostly considered as a negative regulator of T cell activation during immune responses. It is currently unknown whether CD152 can also influence chemokine-driven T cell migration.
  
  
  RESULTS
  We analyzed the consequences of CD152 signaling on Th cell migration using chemotaxis assays in vitro and radioactive cell tracking in vivo. We show here that the genetic and serological inactivation of CD152 in Th1 cells reduced migration towards CCL4, CXCL12 and CCL19, but not CXCL9, in a G-protein dependent manner. In addition, retroviral transduction of CD152 cDNA into CD152 negative cells restored Th1 cell migration. Crosslinking of CD152 together with CD3 and CD28 stimulation on activated Th1 cells increased expression of the chemokine receptors CCR5 and CCR7, which in turn enhanced cell migration. Using sensitive liposome technology, we show that mature dendritic cells but not activated B cells were potent at inducing surface CD152 expression and the CD152-mediated migration-enhancing signals. Importantly, migration of CD152 positive Th1 lymphocytes in in vivo experiments increased more than 200% as compared to CD152 negative counterparts showing that indeed CD152 orchestrates specific migration of selected Th1 cells to sites of inflammation and antigenic challenge in vivo.
  
  
  CONCLUSIONS
  We show here, that CD152 signaling does not just silence cells, but selects individual ones for migration. This novel activity of CD152 adds to the already significant role of CD152 in controlling peripheral immune responses by allowing T cells to localize correctly during infection. It also suggests that interference with CD152 signaling provides a tool for altering the cellular composition at sites of inflammation and antigenic challenge.
authors.affiliation: Experimentelle Pädiatrie, Universitätskinderklinik, Otto-von-Guericke Universität, Magdeburg, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Knieke
authors.forename: Holger
authors.initials: H
authors.lastname: Hoff
authors.forename: Frank
authors.initials: F
authors.lastname: Maszyna
authors.forename: Paula
authors.initials: P
authors.lastname: Kolar
authors.forename: Arnhild
authors.initials: A
authors.lastname: Schrage
authors.forename: Alf
authors.initials: A
authors.lastname: Hamann
authors.forename: Gudrun F
authors.initials: GF
authors.lastname: Debes
authors.forename: Monika C
authors.initials: MC
authors.lastname: Brunner-Weinzierl
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D060908:CTLA-4 Antigen; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D054407:Chemokine CCL4 / Q000494:pharmacology; D054377:Chemokine CXCL12 / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D019713:Receptors, CCR5 / Q000378:metabolism; D054400:Receptors, CCR7 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology
chemical_list: D015703:Antigens, CD; D060908:CTLA-4 Antigen; D054407:Chemokine CCL4; D054377:Chemokine CXCL12; C556707:Ctla4 protein, mouse; C515256:Cxcl12 protein, mouse; D019713:Receptors, CCR5; D054400:Receptors, CCR7; D007371:Interferon-gamma; D019206:GTP-Binding Protein alpha Subunits, Gi-Go