The lung airway epithelium represents a giant surface area in direct contact with external pathogens. This application will investigate what cells are involve din protections against the pathogens, how they get to the lung, where they go in the lung and what they do when they arrive at their destination. T cell receptor transgenic CD8 T cells, specific for a flu hemagglutinin peptide will be used to investigate how they respond to pulmonary viral challenge and how they interact with other components of the innate and acquired immune defense system. The goal is to determine, on the one hand, the mechanism of CD8 cell protection against infection with influenza virus and, on the other hand,, the mechanism of CD8 mediated lung damage.
AIM 1 will study the regulation of lymphocyte entry into the lung and homing to sites within the lung of five populations of antigen specific CD8 T cells (naive CD8 T cells, Tc1 and Tc2 CD8 effectors and Tc1 and Tc2 CD8 memory cells) following their fate in lung sections, draining lymph nodes and spleen using Thy-1 allelic markers, the CFSE """"""""tracker"""""""" dye and BrdU uptake, in the presence or absence of viral challenge. The questions are; which events are antigen specific? What is the role of inflammatory agents? Which cytokines and chemokines are involved in entry into the lung? These events will be correlated with the ability of comparable numbers of the various transferred cells to provide protection, to clear the virus and to maintain effective lung function.
AIM 2 will study how these same five populations of CD8 T cells effect the recruitment of host macrophages, neutrophils and eosinophils into the lung and correlate how these events affect the degree of immunity provided AIM 3 will study the interactions of CD8 T cells with CD4 cells in the response. How do Th1 or Th2 CD4 effectors affect the response of naive CDF8? Is there synergy between CD4 and CD8 T cells? Can the findings with cells from TcR transgenic mice be generalized to other T cells? The results of these studies will lead to the development of more effective adoptive therapy protocols.
