The Role of Tyrosine Kinase Itk in T helper 17 and T regulatory cells in 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. Itk is required for the development of Th17 cells and their production of IL17A in allergic lung inflammation. Furthermore, Type I regulatory and Foxp3+ T regulatory (Tregs) cells, producers of IL10, are positively and negatively regulated by Itk respectively. Farmer’s lung, a subset of hypersensitivity pneumonitis, develops due to repeated exposure to the bacteria Saccharopolyspora rectivirgula (SR) and is dependent on IL17A and regulated by IL10. Surprisingly, exposure to SR drives robust CD4+ T cell IL17A response even in the absence of Itk, with pulmonary inflammation. Transcriptomic analysis of sort purified WT and Itk−/− IL17A producing CD4+ T cells from SR-exposed mice revealed an enrichment of Notch signaling pathway in the absence of Itk. SR also induced the Itk independent development of a population of IL17A producing Foxp3+ Tregs cells, and a significant decrease in IL10 producing Tr1 cells. These data suggest that Itk regulates the expression of IL10, and pathogenic Th17 cells via Notch signaling. These studies suggest that TCR signaling through Itk differentially regulates the development of inflammatory Th17 cells and suppressive Tregs and Tr1 cells in response to SR exposure. Understanding how Itk modulates the development of Th17/Treg cytokine responses will allow us to better understand the precise role of Itk in the regulating the balance of pro- and anti-inflammatory cytokine production during airway inflammation.