Human Natural Killer Cells Mediate Killing of IntracellularMycobacterium tuberculosisH37Rv via Granule-Independent Mechanisms

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Abstract
Despite the continued importance of tuberculosis as a world-wide threat to public health, little is known about the mechanisms used by human lymphocytes to contain and kill the intracellular pathogenMycobacterium tuberculosis. We previously described an in vitro model of infection of human monocytes (MN) with virulentM. tuberculosisstrain H37Rv in which the ability of peripheral blood lymphocytes to limit intracellular growth of the organism could be measured. In the current study, we determined that lymphocyte-mediated killing of intracellularM. tuberculosisoccurs within the first 24 h of coculture with infected MN. Natural killer (NK) cells isolated from both purified protein derivative (PPD)-positive and PPD-negative subjects were capable of mediating this early killing of intracellular H37Rv. NK cell-mediated killing of intracellularM. tuberculosiswas not associated with the production of gamma interferon. Transferred supernatants of cocultured NK cells andM. tuberculosis-infected MN could not mediate the killing of intracellularM. tuberculosis, and Transwell studies indicated that direct cell-to-cell contact was required for NK cells to mediate the killing of the organism. Killing was not dependent upon exocytosis of NK cell cytotoxic granules. NK cells induced apoptosis of mycobacterium-infected MN, but neither killing of intracellularM. tuberculosisby NK cells nor NK cell-induced apoptosis of infected MN was inhibited by blocking the interaction of FasL and Fas. Thus, human NK cells may mediate killing of intracellularM. tuberculosisvia alternative apoptotic pathways.

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