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

Abstract

Abstract Influenza (flu) infections cause 250,000 deaths and 3–5 million cases of severe illness during the average flu season. Severe influenza infections are associated with a combination of strong pro-inflammatory and weak anti-inflammatory immune responses. Production of the anti-inflammatory cytokine IL-10 by T cells restricts immunopathology during flu infections, however our knowledge of the signaling pathways regulating IL-10 induction 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 the development of IL-10-producing CD8+ T cells during influenza A infection. Compared to wild type (WT) mice, Itk−/− mice displayed increased morbidity and mortality after influenza infection, accompanied by a significant reduction of IL-10 producing CD8+ T cells in the airways. Using the model antigen ovalbumin (OVA) and transgenic TCR specific for OVA in CD8+ T cells (OTI), along with an allele sensitive mutation in the ITK kinase domain, we determine that ITK regulates IL-10 production in antigen-specific CD8+ T cells in a kinase dependent manner. RNA sequencing and multiparametric flow cytometric analyses revealed that ITK differentially regulates the expression of cell surface markers and transcription factors that are involved in regulating T cell differentiation, effector and memory phenotypes. Together, our data suggests that ITK is a critical regulator of IL-10 production by CD8+ T cells and regulate immunopathology during influenza infection. Modulating ITK signaling may be a strategy for regulating immunopathology due to viral infections.