Am. J. Respir. Crit. Care Med., Volume 158, Number 2, August 1998, 395-403

CD4⁺ T Cell and Natural Killer Cell-dependent Killing of Mycobacterium tuberculosis by Human Monocytes

TAKAHIRO YONEDA and JERROLD J. ELLNER

Department of Medicine, Case Western Reserve University, and University Hospitals, Cleveland, Ohio; and Second Department of Internal Medicine, Nara Medical University, Nara, Japan

We established an in vitro model of the phagocytosis of Mycobacterium tuberculosis by human peripheral blood monocytes to evaluate the subsequent inhibition of intracellular replication of the organism. Highly purified T cells (94% CD3⁺/CD16) or natural killer (NK) cells (96% CD16⁺/CD3) isolated by Percoll discontinuous density gradient of peripheral blood mononuclear cells were incubated with M. tuberculosis-infected monocyte monolayers. Monocytes were lysed immediately and at 4, 7, and 10 d after infection for quantification of intracellular replication, which was assessed by quantitative plating techniques as colony-forming units (CFU). Whereas control monocytes permitted intracellular replication, T cells activated monocytes to kill 77% (p < 0.01) of intracellular M. tuberculosis compared with control monocytes by 10 d after infection. NK cells activated monocytes to kill 84% (p < 0.01) of M. tuberculosis in comparison with control monocytes. Lymphokine (IL-2)-activated-killer (LAK) cells were capable of activating monocytes to kill 97% (p < 0.01) of the intracellular organisms compared with control monocytes. In purified protein derivative (PPD)-positive donors, PPD-specific-CD4⁺ lymphocytes stimulated monocytes to kill intracellular M. tuberculosis in a Class II major histocompatibility complex-restricted manner. In contrast, in PPD-negative donors, CD4 lymphocytes activated monocytes in a genetically unrestricted manner. Both T cell supernatant and NK cell supernatant generated from cocultivation with M. tuberculosis-infected monocytes also activated monocytes to augment mycobactericidal function. In conclusion, T cells, NK cells, LAK cells, and their supernatants activated mycobactericidal function of monocytes, although these pathways of activation differed in terms of antigenic specificity and genetic restriction.

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