REGULATION OF PRIMARY T CELL RESPONSES TO INTRACELLULAR INFECTION IN THE LUNG

Abstract

<p>Pulmonary infections caused by viruses, bacteria, mycobacteria and fungi, are a leading cause of death world-wide. Intracellular pathogens such as influenza virus and <em>M.tb</em> live inside host cells, making it difficult for the host to eliminate the pathogen. Adaptive T cell immune responses are required to clear intracellular pathogens. Rapid T cell priming and recruitment of effector T cells to the lung is critical to eliminating the pathogen and ultimately host survival, however, unchecked T cell responses can be detrimental. The research in this thesis examines T cell priming during pulmonary intracellular infections and examines the consequences of impaired/enhanced T cell responses at the lung mucosa.</p> <p><em>M.tb</em>, the bacterium that causes tuberculosis evades detection by the host and delays T cell priming. This delay is believed to allow <em>M.tb</em> to establish chronic infection. We show that DAP12 deficient mice prime T cell responses days sooner than wt controls, resulting in enhanced control of virulent <em>M.tb</em>. Enhanced T cell priming in DAP12 deficient mice is due to increased antigen presentation by professional antigen presenting cells in the local draining lymph nodes. These findings indicate that accelerating antigen presentation in the lymph node and T cell priming can dramatically improve host resistance to tuberculosis infection.</p> <p>Influenza infection in DAP12 deficient hosts also results in enhanced T cell activation however caused lethal lung pathology. We identified a previously unidentified role for CD4 T cells expressing FasL causing immunopathology. Furthermore, we show that DAP12 deficient antigen presenting cells are responsible for priming hyperactivated CD4 T cells and contribute to influenza mortality.</p> <p>Because T cell responses are so important in host defence against intracellular infection we examined the feasibility of using ex-vivo manipulated antigen presenting cells as a vaccine to generate T cell responses in the lung. Collectively these findings shed light on the factors which regulate host immune responses in the lung following intracellular infection and provide evidence that antigen presenting cells can be manipulated ex-vivo to elicit protective immune responses at the lung mucosa.</p>