Arhgef1 is required by T cells for the development of airway hyperreactivity and inflammation

Jeanette P. Brown, Christian Taube, Nobuaki Miyahara, Toshiyuki Koya, Roberta Pelanda, Erwin W. Gelfand, Raul M. Torres

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

Abstract

Rationale: 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. Objectives: 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. Measurements and Main 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.

Original languageEnglish
Pages (from-to)10-19
Number of pages10
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume176
Issue number1
DOIs
Publication statusPublished - Jul 1 2007
Externally publishedYes

Keywords

  • Airway hyperreactivity
  • Cytokines
  • Lung inflammation
  • T cells

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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