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IL-22 Produced by Human NK Cells Inhibits Growth of Mycobacterium tuberculosis by Enhancing Phagolysosomal Fusion¹

Rohan Dhiman,^* Mohanalaxmi Indramohan,^* Peter F. Barnes,^* Ramesh C. Nayak, Padmaja Paidipally,^* L. Vijaya Mohan Rao, and Ramakrishna Vankayalapati^2*

*Center for Pulmonary and Infectious Disease Control, Departments of Microbiology and Immunology and Medicine, Biochemistry, Center for Biomedical Research, University of Texas Health Center, Tyler, TX 75708

We determined whether human NK cells could contribute to immune defenses against Mycobacterium tuberculosis through production of IL-22. CD3^–CD56⁺ NK cells produced IL-22 when exposed to autologous monocytes and -irradiated M. tuberculosis, and this depended on the presence of IL-15 and IL-23, but not IL-12 or IL-18. IL-15-stimulated NK cells expressed 10.6 times more DAP10 mRNA compared with control NK cells, and DAP10 siRNA inhibited IL-15-mediated IL-22 production by NK cells. Soluble factors produced by IL-15-activated NK cells inhibited growth of M. tuberculosis in macrophages, and this effect was reversed by anti-IL-22. Addition of rIL-22 to infected macrophages enhanced phagolysosomal fusion and reduced growth of M. tuberculosis. We conclude that NK cells can contribute to immune defenses against M. tuberculosis through production of IL-22, which inhibits intracellular mycobacterial growth by enhancing phagolysosomal fusion. IL-15 and DAP-10 elicit IL-22 production by NK cells in response to M. tuberculosis.

² Address correspondence and reprint requests to Dr. Ramakrishna Vankayalapati, Center for Pulmonary Infectious Disease Control, University of Texas Health Center, 11937 U.S. Highway 271, Tyler, TX 75708-3154. E-mail address: Krishna.vankayalapati{at}uthct.edu

¹ This work was supported by grants from the National Institutes of Health (AI054629, A1073612, and A1063514), the Cain Foundation for Infectious Disease Research, and the Center for Pulmonary and Infectious Disease Control. Peter F. Barnes holds the Margaret E. Byers Cain Chair for Tuberculosis Research.