Respiratory virus infections are a major cause of morbidity and mortality worldwide and there is an urgent need to improve current vaccines against these pathogens. CD8+ cytotoxic T lymphocytes (CTL) play a central role in controlling primary respiratory virus infection and are the foundation of heterotypic immunity against secondary infections. However, relatively little is known about the induction, persistence, and recall of CD8+ T cell responses to infections at mucosal surfaces, such as the lung, and the relationship to heterotypic immunity.. In the current proposal, two well-established murine models of respiratory virus infections (Sendai virus and influenza virus) will be used to investigate the recall of antigen-specific CD8+ T cell responses. The preliminary data shown that substantial numbers of antigen-specific T cells persist not only in the spleen and local draining lymph nodes, but also in the lung tissue and airways following respiratory virus infection. Interestingly, memory CD8+ T cells in the lungs differ from those observed in the spleen in terms of phenotype, relative frequency, and longevity. The identification of distinct populations of memory CD8+ T cells raises a number of questions regarding the relative contributions of memory cell subsets to recall responses. And protective heterotypic immunity in general. Thus, the overall goal of this proposal is to understand the induction, distribution, and recall of CD8+ memory T cells to respiratory infections with a view to improving vaccine design.
Aim 1 will further characterize antigen-specific CD8+ memory T cell sin the lungs to determine (i) their phenotypic and functional characteristics, (ii) their basal proliferation rates in vivo, and (iii) the factors that impact their maintenance in the lung. Detailed information on the nature of Antigen- specific T cells memory cells in the lung is important for understanding heterotypic immunity in general.
Aim 2 will investigate the relationship between distinct populations of memory cells and the recall responses to infection in the lung. The studies will focus on clearly defined sub- populations of antigen-specific memory cells that persist in either the lungs or the spleen.
Aim 3 will investigate the distribution and phenotypes of memory CD8+ T cells elicited by different vaccine strategies, and their relative efficacy in a recall response. Particular emphasis will be placed on strategies that induce mucosal immunity in the lung. Taken together, these studies will generate detailed information on the relationship between memory T cell populations and protective heterotypic immunity at a mucosal surface. A thorough understanding of the cellular immune response to infection in the lung is essential for future vaccine development.
