Antigen presenting cells, both dendritic cells and monocytes, will be evaluated in two diseases of cell mediated immunity: AIDS and tuberculosis. Immunological studies of HIV-1 infection aim to identify a) causes of CD4+ T cell depletion and b) pathways for immunotherapy and prophylaxis. We find that dendritic cells are not readily infected by HIV- 1 but serve as vehicles for vigorous cytopathic infections, transmitting HIV-1 to CD4+ T cells that are responding to antigens being presented by the APCs. To extend this finding we will test if dendritic cells in other sites [skin, inflammatory exudate] resist infection with HIV-1 but transmit virus to T cells. We will evaluate if the HIV-1 that is associated with dendritic cells is sequestered intracellularly for long periods and in a CD4-dependent fashion. Since there is massive release of virions during the APC-T cell interaction, we will test if antigen-nonspecific memory cells in the environment undergo latent infection that can be activated upon subsequent encounter with specific antigen. This scenario would explain how a small amount of HIV-1 that is carried by dendritic cells to T cells in one immune response may sensitize large numbers of memory T cells for an ultimate cytopathic infection. Since recently infected individuals may use HIV-1 specific T cells to clear the initial viremia, we will perform a clinical study in which we look for cells that block transmission of HIV-1 from dendritic cells to T cells and that kill infected monocytes. Analogous aims embrace our studies of TB. Mycobacteria persist in monocytes, whereas dendritic cells may be important for generating protective T cells. With methods developed in this subproject, we will use dendritic cells to efficiently adsorb and expand mycobacterial reactive T cell clones from the blood of patients that are recovering from TB. The clones will be selected for reactivity with monocytes that harbor replicating M.tub. We will test if the clones can reduce bacillary burden within the monocytes either by a cytolytic or noncytolytic mechanism. Mycobacterial proteins being presented to such clones will be identified. We will test if there is transfer of epitopes from infected monocytes to poorly phagocytic dendritic cells. Our hypothesis is that optimal immunity requires epitopes that are presented by dendritic cells to those T cells that resist mycobacteria within infected monocytes.
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