Guanine nucleotide-binding proteins of the G12 family shape immune functions by controlling CD4+ T cell adhesiveness and motility

Susanne Herroeder; Peter Reichardt; Antonia Sassmann; Barbara Zimmermann; Dagmar Jaeneke; Jana Hoeckner; Markus W Hollmann; Klaus-Dieter Fischer; Stephan Vogt; Robert Grosse; Nancy Hogg; Matthias Gunzer; Stefan Offermanns; Nina Wettschureck

doi:10.1016/j.immuni.2009.02.010

Guanine nucleotide-binding proteins of the G12 family shape immune functions by controlling CD4+ T cell adhesiveness and motility

Immunity. 2009 May;30(5):708-20. doi: 10.1016/j.immuni.2009.02.010. Epub 2009 Apr 30.

Authors

Susanne Herroeder¹, Peter Reichardt, Antonia Sassmann, Barbara Zimmermann, Dagmar Jaeneke, Jana Hoeckner, Markus W Hollmann, Klaus-Dieter Fischer, Stephan Vogt, Robert Grosse, Nancy Hogg, Matthias Gunzer, Stefan Offermanns, Nina Wettschureck

Affiliation

¹ Institute of Pharmacology, University of Heidelberg, 69120 Heidelberg, Germany.

PMID: 19409815
DOI: 10.1016/j.immuni.2009.02.010

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
CD4-Positive T-Lymphocytes / cytology
CD4-Positive T-Lymphocytes / enzymology
CD4-Positive T-Lymphocytes / immunology*
Cell Adhesion / immunology
Cell Movement / immunology
Cell Proliferation
Dendritic Cells / cytology
Dendritic Cells / immunology*
Dendritic Cells / metabolism
GTP-Binding Protein alpha Subunits, G12-G13 / genetics
GTP-Binding Protein alpha Subunits, G12-G13 / immunology
GTP-Binding Protein alpha Subunits, G12-G13 / metabolism*
Intercellular Adhesion Molecule-1 / immunology
Intercellular Adhesion Molecule-1 / metabolism
Lymphocyte Function-Associated Antigen-1 / immunology
Lymphocyte Function-Associated Antigen-1 / metabolism*
Mice
Mice, Inbred C57BL
Mice, Knockout
Neuropeptides / immunology
Neuropeptides / metabolism
Signal Transduction / immunology
Telomere-Binding Proteins / immunology
Telomere-Binding Proteins / metabolism
Vascular Cell Adhesion Molecule-1 / immunology
Vascular Cell Adhesion Molecule-1 / metabolism
rac GTP-Binding Proteins / immunology
rac GTP-Binding Proteins / metabolism
rac1 GTP-Binding Protein
rhoA GTP-Binding Protein / immunology
rhoA GTP-Binding Protein / metabolism

Substances

Lymphocyte Function-Associated Antigen-1
Neuropeptides
Rac1 protein, mouse
Rif1 protein, mouse
Telomere-Binding Proteins
Vascular Cell Adhesion Molecule-1
Intercellular Adhesion Molecule-1
GTP-Binding Protein alpha Subunits, G12-G13
rac GTP-Binding Proteins
rac1 GTP-Binding Protein
rhoA GTP-Binding Protein