The lung is the primary portal of infection with Mycobacterium tuberculosis (MTB), the cause of human tuberculosis. The ability of MTB to infect and persist in the face of adaptive immunity in the lung is the hallmark of this pathogen. Class II major histocompatibility antigen (MHC-II) restricted CD4+ T cells and their requisite antigen presenting cells (ARC), dendritic cells (DC) and macrophages, are essential for protective immunity. How MHC-II restricted CD4+ T cell responses are generated in the lung during MTB infection is difficult, if not impossible, to address in humans. Murine models of pulmonary MTB infection are well-suited for analysis of the interactions between pulmonary ARC and CD4+ T cells. In addition, mechanisms used by MTB to resist the host and survive in the lung also are readily analyzed in mice. The outcome of the interaction between MTB and CD4+ T cells in the lung is determined by the balance between the lung's ability to optimally process and present MTB antigens for MHC-II restricted CD4+ T cells, and MTB's ability to inhibit CD4+ T cell responses. The relative importance of MTB's activating and inhibitory mechanisms for CD4+ T cells will differ depending on the stage of infection, i.e. early, acute primary vs. chronic persistent infection. There are three specific aims to address this hypothetical model: 1. To determine the ability of lung antigen presenting cells (alveolar macrophages, CD11c+ARC subsets) to activate naive and memory MHC-II restricted CD4+ T cells, and the ability of M. tuberculosis lipoproteins (LpqH, LprA, LprG) and TLR-2 to modulate lung ARC function; 2. To determine the molecules and mechanisms used by M. tuberculosis to directly inhibit naive and effector/memory CD4+ T cell activation and function in the lung; 3. To use CD4+ MTB 85B- and ovalbumin-specific TCR transgenic mice to determine during M. tuberculosis infection the in vivo mechanisms of naive and effector/memory CD4+ T cell activation and the role(s) of lung ARC in this activation. Better understanding of counterbalancing activating and inhibitory immune mechanisms in the lung will provide insight into basic mechanisms of mycobacterial immune evasion and aid in developing improved vaccines and immuno-therapies for tuberculosis. ? ? ?
