Tuberculosis(TB) remains a common cause of death, and is the most common copathogen in HIV-associated deaths worldwide. The limitations of drug therapy have increased the interest in developing new vaccines for TB, and improved understanding of immunity to TB is essential for development of improved vaccines. While a role for T lymphocytes in immunity to TB is well established, the mechanisms of initiation of adaptive immunity to M. tuberculosis(Mtb) are not well understood. In particular, the specific contributions of macrophages and dendritic cells to initiation of immunity to Mtb are not known. We have found that immunity to Mtb in mice depends on recruitment of macrophages and dendritic cells to the lungs and to the mediastinal lymph node, which drains the lungs. We have also found that mice with a dendritic cell-selective defect in MHC class II antigen presentation exhibit defective CD4+ T cell responses to Mtb. We hypothesize that macrophages and dendritic cells play distinct roles in initiation of immunity to Mtb, that dendritic cells transport intact Mtb from the lung to the mediastinal lymph node, and that the mediastinal lymph node plays a dominant role in the immune response to Mtb. We will use novel procedures and mutant mice to test these hypotheses. We will characterize the immune response to Mtb in mice with a dendritic cell-selective defect in class II antigen presentation, to determine whether dendritic cells are essential for initiation of immunity to Mtb. We will use immunohisto chemistry and flow cytometry, with Mtb expressing heterologous markers, to determine the rates of infection of macrophages and dendritic cells in the lung, mediastinal lymph node, and spleen, and will test the hypothesis that dendritic cells transport Mtb from the lung to the mediastinal lymph node, by a mechanism that depends on the chemokines CCL19 and CCL21, and their receptor, CCR7. We will also quantitate the CD4+T cell response in the mediastinal lymph node and spleen, to determine the relative contributions of these organs to TB immunity. We will perform in vitro studies to determine whether dendritic cells are uniquely able to prime naive T lymphocytes to respond to antigens expressed by Mtb, and we will test the hypothesis that macrophages modify dendritic cell-dependent initiation of immunity to Mtb. These studies will provide a foundation for studies to target candidate vaccines to specific antigen-presenting cells, and will provide a basis for studies of variable immune responses to natural infection with M. tuberculosis.
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