ITK regulates antigen-specific CD8+ T cell-derived IL-10 production and modulates influenza-induced pulmonary immunopathology

Abstract

Abstract Influenza (flu) infection is a leading cause of respiratory disease and death worldwide, causing 3-5 million cases of severe illness and more than 250,000 deaths during an average flu season. Severe life-threatening influenza infections in humans are accompanied by an aggressive pro-inflammatory response and an insufficient anti-inflammatory immunity. The production of the immunosuppressive cytokine IL-10 by virus-specific T cells is critical in limiting the immunopathology during flu infection, however, our understanding of how this immunomodulatory event is regulated at the molecular level is very limited. Using mouse models that report the production of IL-10 through green fluorescent protein, OTI CD8+ T cells and influenza A viruses that express the OTI antigen ovalbumin (OVA), we find that the T cell receptor (TCR) responsive tyrosine kinase, Interleukin-2 Inducible T cell kinase (ITK), is a critical regulator of the ability of CD8+ T cells to develop into IL-10-producing cells in an antigen specific manner. The absence of ITK resulted in increased morbidity and mortality in murine model post influenza A infection, accompanied by a severe impairment of IL-10 production by CD8+ T cells in the airway. ITK kinase activity is required for its role in promoting IL-10-producing CD8+ T cell differentiation, by regulating the levels of expression of transcription factors including IRF4, Blimp1, AHR and cMAF. Our data suggest that ITK regulates CD8+ T cell production of IL-10 during influenza A infection, and modulates the development of pulmonary immunopathology. Targeting ITK signaling maybe a promising strategy in modulating airway inflammation during viral infections.