The role of tyrosine kinase Itk in T helper 17 and T regulatory cells in IL17 mediated hypersensitivity pneumonitis

Abstract

Abstract The balance of inflammatory and suppressive cytokines is critical in controlling inflammatory responses, and the pro- and anti-inflammatory cytokines IL17A and IL10 has been implicated in numerous pulmonary inflammatory diseases. The tyrosine kinase, Itk, plays a critical role in T cell activation. We have previously shown that Itk−/− mice do not develop allergic airway disease coupled with reduced production of IL17A in the lungs. In vitro, Itk is required for the development of Th17 cells and their production of the pro-inflammatory cytokine IL17A. Furthermore, Type I regulatory and Foxp3+ T regulatory (Tregs) cells, suppressive producers of IL10, are positively and negatively regulated by Itk respectively. Farmer’s lung is a subset of hypersensitivity pneumonitis caused by repeated exposure to the bacteria Saccharopolyspora rectivirgula (SR), and is dependent on IL17A and regulated by IL10. We find that surprisingly, 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. SR also induced Itk independent development of a population of population of Foxp3+ Tregs cells that produce IL17A, accompanied by a significant decrease in Tr1 cells compared to WT mice. These studies suggest that TCR signaling through Itk differentially regulates the development of inflammatory Th17 cells and suppressive Tregs and Tr1 cells. Understanding how Itk modulates the development of Th17/Treg cytokine responses will allow us to better understand the precise role of Itk in the production of IL17A and IL10 in airway inflammation.