CD4 T Cell Protection and Pathology in the Lung. The lung is the major site of entry of airborne or inhaled pathogens and effective immune responses wherein are necessary to destroy infectious agents before they can spread. However the lungs are a delicate web of airways and damage to the epithelium either by direct T cell mediated lysis or via indirect effect of inflammatory responses which can impede oxygen exchange and contribute to mortality. CD4 T cells are the major immunoregulatory cell, promoting inflammation, helping B cells develop into antibody-secreting cells, helping CD4 T cell develop into cytotoxic cells, activating macrophages to become cytolytic and enhancing their abilities to clear infection and responses. The major actions of CD4 T cells are mediated by the cytokines they produce. Importantly, T cells can become polarized to produce two major patterns of cytokines-type 1 and type2 which have very different functions. The major actions of CD4T cell are mediated by the cytokines-type1 and type2 which have very different functions. We will use a model of influenza virus infection in the lung to determine what roles different subsets of CD4T cells play both in protection against the virus and in pathology which leads to compromised lung function and death. We will use a transgenic mouse model where each CD4T cell has the same receptor specific for influenza hemagglutinin presented by the IA/d MHC molecule. From these mice we will isolate pure antigen- unexpected CD4T cells (naive) and from that population activated """"""""effector"""""""" cells which have type 1 or 2 polarized pattern of cytokine production lethal infection with influenza.
In Aim 1, we will determine the kinetics and specific of recruitment of T cell subsets into the lung and determine if selected chemokines and adhesion molecules are required. We will follow the division and expansion of CD4T responding to virus, using recently developed vital dyes.
In Aim 2 we will determine the ability of CD4T cell subsets to provide protection against lethal effects of virus and will analyze whether protective effects which prolong survival and lead to viral clearance, are due to CD4 T cells either helping IFNgamma in these effects and we will investigate roles CD4T ells and the cytokines they produce play in immunopathology in the lung.
In Aim 3, we will follow the development of CD4 memory cells, and determine their localization and functional abilities and we will prepare memory cells and transfer them to costs to examine the potential of memory cells to mediate protection. The insights gained from these experiments will provide critical information about which kinds of immune responses are best able to provide protection from virus and which are most likely to lead to pathology. Together with the results from other Projects in this program, we expect to learn what strategies will be useful to enhance immunity to pathogens which infect the lung.
