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. While flu vaccines are effective at reducing the morbidity and mortality of flu infections, clearance of virus relies on the development of a strong immune response, which can also cause immunopathology. Severe influenza diseases that are life-threatening in human patients are accompanied by an aggressive pro-inflammatory response and an insufficient anti-inflammatory immunity. This makes this work highly significant. The production of the immunosuppressive cytokine IL-10 by viral specific CD8+ T cells is critical in limiting the immunopathology during flu infection, however the timing of this IL-10 production is critical. If it is produced to early, it suppresses the effector immunity, but if it is produced to late, immunopathology and morbidity will result. Understanding how IL-10 production by CD8+ T cells is regulated is critical for understanding how to control flu-induced lung immunopathology, however, this is not yet clear. Based on our results, we have developed the hypothesis that ITK regulates the development of IL-10- producing CD8+ T cells, thus controlling immunopathology during influenza A infection. We propose experiments in two specific aims to determine the role of the TCR/ITK signaling in the development and immunomodulatory function of IL-10-producing CD8+ T cells during Influenza A infection. This work is highly innovative as we utilize novel and unique transgenic mouse models, well- established approaches and a pharmaceutically traceable target, and have exciting preliminary data that will be expanded to provide information on a signaling pathway for better understanding of how IL-10 is regulated in virus-specific T cells to control virus-induced immunopathology, morbidity and mortality. Completion of the proposed research will generate essential data and information set to support submission of a larger scale grant application in the R01 level to the NIH. As one of the specific research projects integrated in the ongoing program to establish the Center for Lung Biology and Disease, this project investigating the molecular mechanisms through which IL-10- poducing CD8+ T cells modulate flu-induced lung immunopathology is in perfect alignment with the program mission. The project PI will be a key member of the group to contribute to the establishment of a Center of Biomedical Research Excellence (COBRE) in Lung Biology and Disease. This project will contribute to the development and benefit from the usages of Pulmonary Immunopathology, Molecular Biology, and Mouse Maintenance cores.
