ROLE OF THE MONONUCLEAR PHAGOCYTE AS AN ANTIGEN-PRESENTING CELL FOR HUMAN GAMMA-DELTA-T-CELLS ACTIVATED BY LIVE MYCOBACTERIUM-TUBERCULOSIS

Gamma-delta T cells, both human and murine, have been found to be highly responsive to mycobacterial antigens. However, the role and function of gamma-delta T cells in the immune response to Mycobacterium tuberculosis remain largely unknown. In earlier studies, we demonstrated that monocytes infected with live M. tuberculosis were particularly effective inducers of human peripheral blood gamma-delta T cells. The present studies were performed to further characterize the interaction between human mononuclear phagocytes, gamma-delta T cells, and live M. tuberculosis, in comparison with CD4+ T cells. First, we found that resting gamma-delta T cells expanded in vitro by live M. tuberculosis were specific for M. tuberculosis, and that heat killing and washing the mycobacteria removed the antigen(s) for gamma-delta T cells. In contrast, the heat-killed mycobacteria retained significant antigenicity for CD4+ T cells. Second, live M. tuberculosis-expanded gamma-delta T cells from healthy tuberculin-positive donors did not respond significantly to the antigens in M. tuberculosis culture filtrate, including the 65- and 71-kDa mycobacterial heat shock proteins. Third, the activation of gamma-delta T cells by live mycobacteria was dependent on antigen-presenting cells, and mononuclear phagocytes were found to be very efficient antigen-presenting cells both for resting peripheral blood gamma-delta T cells and for activated expanded gamma-delta T cells. The mononuclear phagocyte carried the necessary costimulatory factors necessary for gamma-delta T-cell proliferation. Fourth, the antigen repertoire and HLA requirements for CD4+ memory T cells and those for gamma-delta T cells appear to be quite distinct from each other. CD4+ T cells recognized both soluble protein antigens and whole organisms in a class II major histocompatibility complex-restricted manner, whereas gamma-delta T cells appeared to recognize only constituents associated with the whole organism and were not restricted by class I or class II major histocompatibility complex molecules. Finally, the assay system described to expand and purify responding CD4+ and gamma-delta T cells after stimulation with live M. tuberculosis represented a simple approach to the direct comparison of these two T-cell populations in the interaction with mononuclear phagocytes infected with M. tuberculosis. Such studies provide insight not only into the relative roles of human CD4+ and gamma-delta T cells in the human immune response to intracellular bacterial pathogens such as M. tuberculosis but also into the basic biologic role of human gamma-delta T cells in antimicrobial immunity.