In humans neither vaccination against- nor previous infection with TB provide solid immunity to re-infection and disease in the lung. In animal models, previous antigen exposure can induce long-lived memory T cells capable of mediating a strong recall response and enhanced control of bacterial growth. As for the human however, this response does not result in protection from disease in the lung. It is the basis of this application that it is not a failure of vaccination to induce potentially protective recall responses but a failure of the natural challenge to recruit that response to the lung which is responsible for the limited efficacy of vaccination against TB. It is currently accepted that antigen-specific, IFN-gamma producing T cells are the primary mediators of macrophage activation and subsequent control of intracellular growth of TB in the lung. It is also the appearance of this type of cell in the recall response that correlates with suppression of bacterial growth. While this response accumulates rapidly in response to systemic challenge it is only slowly expressed in response to challenge via the lung. In this application we will determine the quality and quantity of the long-lived antigen-specific response in order to confirm or refute our hypothesis that strong, potentially protective recall responses are induced both by vaccination and by previous infection. Further, will test our hypothesis that the natural challenge route (i.e. via the lung) results in slow activation and/or recruitment of the existing antigen-specific recall response. Finally we will determine the ability of the recall response to protect the host from the consequences of TB infection in the lung. Identification of the factors responsible for the slow response to TB infection following aerosol exposure will contribute to the design of a vaccine that induces cells capable of overcoming these factors.