This proposal is designed to investigate the mechanism of action of CD4+ T lymphocytes in the process of recovery from experimental pulmonary virus infection and in the expression of pulmonary injury. It focuses on the role of specific CD4+ T lymphocyte effector activities, notably cell mediated cytotoxicity and IL-4 production, in virus clearance and in suppression of the host response to infection. The experiments outlined are an outgrowth of our ongoing analysis of the in vivo function of virus specific T lymphocytes in pulmonary virus infection in the mouse. The experimental design employs clonal populations of CD4+ T lymphocytes directed to type A influenza virus with defined patterns of lymphokine production characteristic of Th1 T lymphocytes, Th2 T lymphocytes and CD4+ T lymphocyte populations of intermediate phenotype. The cloned CD4+ T cell populations are used in an adoptive transfer model of experimental influenza infection in mice. This analysis will be complimented by studies with """"""""knock out"""""""" mice genetically deficient in specific lymphocyte effector activities, e.g. IL-4, lL-5 or interferon-y production. In addition, efforts will focus on the characterization of a model for T lymphocyte mediated pulmonary injury using transgenic mice expressing influenza gene products in the lung off of a lung-specific promoter (human surfactant-C).
The specific aims of the proposed studies are: 1.) To define the contribution of specific T lymphocyte gene products in virus clearance and recovery from experimental type A Influenza infection and 2.) to establish an experimental model of T lymphocyte mediated pulmonary injury. This investigation should provide basic information on the cellular and molecular basis of CD4+ T lymphocyte mediated anti viral activity during pulmonary infection. These studies should also provide new information on the mechanism and pattern of injury produced by T lymphocytes in the lung and may as well provide insight into the role of T lymphocytes in autoimmune diseases of the lung.
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