Itk independent development of natural Th17 cells and IL17A-driven hypersensitivity pneumonitis

Abstract

Abstract The tyrosine kinase, Itk, plays a critical role in T cell receptor signaling, and we have previously shown that Itk is required for the development of Th17 cells and their production of the pro-inflammatory cytokine IL17A. IL17A has been implicated in numerous pulmonary inflammatory diseases. We have previously shown that Itk−/− mice do not develop allergic airway disease coupled with protected reduced production of IL17A in the lungs in a model of allergic asthma. Farmer’s lung is a subset of hypersensitivity pneumonitis caused by repeated exposure to the bacteria Saccharopolyspora rectivirgula (SR). This IL17A-driven disease is characterized by an influx of neutrophils and T lymphocytes. Here we show that a population of natural Th17 cell develop in the absence of Itk. Furthermore, exposure to SR drives robust IL17A response produced by CD4+ T cells even in the absence of Itk, accompanied by the development of pulmonary inflammation. These studies suggest that TCR signaling through Itk differentially regulates the development of conventional and natural Th17 cells. Understanding how Itk modulates the Th17 cytokine responses will allow us to better understand the precise role of Itk in the production of IL17A in airway inflammation.