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

摘要

Although it is known that T cell infiltration of the lung is critical for the development of allergic lung disease, the activation of antigen-specific T cells within the lung environment is not well understood. Arhgef1, an intracellular protein expressed by hematopoietic cells, has been shown to regulate migration and adhesion of diverse leukocyte populations. Using naive Arhgef1-/- mice, we show that Arhgef1 regulates leukocyte homeostasis in the lung. In an antigen-driven murine asthma model, we show that Arhgef1-/- mice display significantly reduced airway hyperreactivity, Th2 cytokine production, and lung inflammation, despite an intact primary systemic immune response. Adoptive transfer of wild type T cells into Arhgef1 -/- mice is found to restore airway hyperreactivity and recruitment of leukocytes to the lung, demonstrating that T cells depend on Arhgef1 to promote lung inflammation. Cultures from isolated leukocytes and tissue explants demonstrated that effector T cells when isolated were capable of generating cytokines, but effector T cells were unable to produce cytokines when confined to either lung or spleen tissue explants. We further show that after airway challenge of Arhgef1-/- mice, antigen-specific T cells are present in mutant lungs but interact with CD11c+ antigen presenting cells at a significantly reduced frequency and likely underlies the inability of Arhgef1-/- mice to mount an adaptive immune response to airway challenge. Overall, the data presented in this thesis indicate that Arhgef1, a regulator of Galpha12/13 and RhoA signaling, plays an important role in regulating effector T cell function required for the development of airway inflammation.