Arhgef1 is required by T cells for the development of airway hyperreactivity and inflammation.
BACKGROUND
Arhgef1 is an intracellular protein, expressed by hematopoietic cells, that regulates signaling by both G protein-coupled receptors and RhoA, and, consequently, is required for appropriate migration and adhesion of diverse leukocyte populations.


OBJECTIVE
To evaluate a possible contribution for Arhgef1 in the development of airway inflammation and airway hyperreactivity.


METHODS
Arhgef1-deficient (Arhgef1-/-) and wild-type (WT) mice were sensitized and airway challenged, followed by measurement of airway responsiveness to inhaled methacholine. Inflammation was assessed by several parameters that included flow cytometric analysis and histology. Arhgef1-deficient recipients were reconstituted with WT T lymphocytes before sensitization and challenge, and again measured for airway responsiveness and inflammation. Cytokine production in response to specific antigen was measured in cultures of isolated leukocytes from lung and spleen and compared with the levels generated in lung and spleen explant cultures.


RESULTS
Arhgef1-/- mice display significantly reduced airway hyperreactivity, Th2 cytokine production, and lung inflammation, despite intact systemic immunity. After airway challenge of Arhgef1-/- mice, antigen-specific T cells were present in mutant lungs, but were found to interact with CD11c+ cells at a significantly reduced frequency. Adoptive transfer of WT T cells into Arhgef1-/- mice restored airway hyperreactivity and inflammation.


CONCLUSIONS
These data demonstrate that T cells depend on Arhgef1 to promote lung inflammation. Moreover, a deficiency in Arhgef1 results in reduced T cell-CD11c+ antigen-presenting cell interaction, and likely underscores the inability of Arhgef1-/- mice to mount an adaptive immune response to airway challenge.
Brown
Jeanette P
JP
Integrated Department of Immunology, University of Colorado at Denver and Health Sciences Center and National Jewish Medical and Research Center, Denver, Colorado 80206, USA.
Taube
Christian
C
Miyahara
Nobuaki
N
Koya
Toshiyuki
T
Pelanda
Roberta
R
Gelfand
Erwin W
EW
Torres
Raul M
RM
D000818:Animals; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000276:immunology*; D001985:Bronchial Provocation Tests; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D020662:Guanine Nucleotide Exchange Factors / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D011014:Pneumonia / Q000139:chemically induced / Q000276:immunology*; D011518:Proto-Oncogene Proteins / Q000276:immunology*; D064067:Rho Guanine Nucleotide Exchange Factors; D013154:Spleen / Q000166:cytology / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*
C577231:Arhgef1 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D011518:Proto-Oncogene Proteins; D064067:Rho Guanine Nucleotide Exchange Factors