ITK regulates IL-10 production by CD8+ T cells and lung immunopathology during influenza infection

Abstract

Abstract Respiratory viral infections are a major cause of human morbidity and mortality. Influenza (flu) infections cause 250,000 deaths and 3–5 million cases of severe illness during the average flu season. Severe flu infections are associated with a combination of strong pro-inflammatory and weak anti-inflammatory immune responses. Production of the immunomodulatory cytokine IL-10 by T cells restricts immunopathology during flu infections, however our knowledge of the signaling pathways regulating IL-10 induction during flu is limited. Using IL-10GFP reporter mouse models, we found that Interleukin-2 inducible T cell kinase (ITK), a critical component in T cell receptor (TCR) signaling, regulates immunopathology and the development of IL-10-producing CD8+ T cells in the airways during influenza A infection. Utilizing alternative coculture, the model antigen ovalbumin (OVA), and transgenic TCR specific for OVA in CD8+ T cells (OTI) adoptive transfer, we determined that ITK regulates flu antigen-specific IL-10+CD8+ T cell differentiation in a CD8+ T cell intrinsic and extrinsic manner. Exogenous IL-2 rescued IL-10 production by Itk−/− CD8+ T cells, in vitro and in vivo, suggesting that ITK may play a role in IL-2-producing T helper cells that promote IL-10 production in CD8+ T cells. The absence of ITK impaired the expression of transcription factors (TFs) IRF4 and Blimp-1, and retroviral transduction enabling the reintroduction of these TFs could partially rescue IL-10 production in Itk−/− CD8+ T cells. Our data suggests that ITK is a critical regulator of IL-10 production by CD8+ T cells and flu-induced pulmonary immunopathology. Modulating ITK signaling may be a strategy for regulating immunopathology due to viral infections.