Guanine nucleotide-binding proteins of the G12 family shape immune functions by controlling CD4+ T cell adhesiveness and motility.
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.
Herroeder
Susanne
S
Institute of Pharmacology, University of Heidelberg, 69120 Heidelberg, Germany.
Reichardt
Peter
P
Sassmann
Antonia
A
Zimmermann
Barbara
B
Jaeneke
Dagmar
D
Hoeckner
Jana
J
Hollmann
Markus W
MW
Fischer
Klaus-Dieter
KD
Vogt
Stephan
S
Grosse
Robert
R
Hogg
Nancy
N
Gunzer
Matthias
M
Offermanns
Stefan
S
Wettschureck
Nina
N
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
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