title: Guanine nucleotide-binding proteins of the G12 family shape immune functions by controlling CD4+ T cell adhesiveness and motility.
abstract: Integrin-mediated adhesion plays a central role in T cell trafficking and activation. Genetic inactivation of the guanine nucleotide-binding (G) protein alpha-subunits Galpha(12) and Galpha(13) resulted in an increased activity of integrin leukocyte-function-antigen-1 in murine CD4(+) T cells. The interaction with allogeneic dendritic cells was enhanced, leading to an abnormal proliferative response in vitro. In vivo, T cell-specific inactivation of Galpha(12) and Galpha(13) caused lymphadenopathy due to increased lymph node entry and enhanced T cell proliferation, and the susceptibility toward T cell-mediated diseases was enhanced. Mechanistically, we show that in the absence of Galpha(12) and Galpha(13) the activity of the small GTPases Rac1 and Rap1 was increased, whereas signaling of the small GTPase RhoA was strongly reduced. Our data indicate that locally produced mediators signal through Galpha(12)- and Galpha(13)-coupled receptors to negatively regulate cell polarization and adhesiveness, thereby fine-tuning T cell trafficking, proliferation, and susceptibility toward T cell-mediated diseases.
authors.affiliation: Institute of Pharmacology, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Herroeder
authors.forename: Peter
authors.initials: P
authors.lastname: Reichardt
authors.forename: Antonia
authors.initials: A
authors.lastname: Sassmann
authors.forename: Barbara
authors.initials: B
authors.lastname: Zimmermann
authors.forename: Dagmar
authors.initials: D
authors.lastname: Jaeneke
authors.forename: Jana
authors.initials: J
authors.lastname: Hoeckner
authors.forename: Markus W
authors.initials: MW
authors.lastname: Hollmann
authors.forename: Klaus-Dieter
authors.initials: KD
authors.lastname: Fischer
authors.forename: Stephan
authors.initials: S
authors.lastname: Vogt
authors.forename: Robert
authors.initials: R
authors.lastname: Grosse
authors.forename: Nancy
authors.initials: N
authors.lastname: Hogg
authors.forename: Matthias
authors.initials: M
authors.lastname: Gunzer
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.forename: Nina
authors.initials: N
authors.lastname: Wettschureck
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D002448:Cell Adhesion / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009479:Neuropeptides / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D034501:Telomere-Binding Proteins / Q000276:immunology / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000276:immunology / Q000378:metabolism; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein / Q000276:immunology / Q000378:metabolism
chemical_list: D016169:Lymphocyte Function-Associated Antigen-1; D009479:Neuropeptides; C484602:Rac1 protein, mouse; C492748:Rif1 protein, mouse; D034501:Telomere-Binding Proteins; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein