Regulation of IL10 production in CD8+ T cells during Flu infection by tyrosine kinase Itk

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Project Summary / Abstract Influenza (flu) infection is the leading cause of respiratory infection, causing 3-5 million cases of severe illness and greater than 500,000 deaths worldwide. While flu vaccines are effective at reducing the mortality and morbidity of flu infections, clearance of virus relies on the development of a strong immune response, which can also cause immunopathology. This makes this work highly significant. The production of the immunosuppressive cytokine IL10 by viral specific CD8+ T cells is critical in limiting the immunopathology during flu infection, however the timing of this IL10 production is critical, too early and it suppresses the immune response, too late and immunopathology and morbidity results. Understanding how IL10 production by CD8+ T cells is regulated is critical for understanding how to control this immunopathology, however, this is incompletely understood. Based on our results, we have developed the hypothesis that Itk regulates the development of IL10-producing CD8+ T cells, thus controlling immunopathology during influenza A infection. We propose experiments in three specific aims that will determine the role of Itk in the development of IL10-producing CD8+ T cells and immunopathology during Influenza A infection, in the suppressive function of IL10-producing CD8+ T cells, and the mechanism by which Itk regulates IL10 production in CD8+ T cells. This work is extremely innovative as we utilize novel and unique transgenic mice and approaches, and have exciting preliminary data that when fleshed out, will provide information on how IL10 is regulated in virus specific T cells to control virus-induced immunopathology, morbidity and mortality.