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Published online October 28, 2009
The Journal of Immunology, 2009, 183, 6639 -6645
Copyright © 2009 by The American Association of Immunologists, Inc.
doi:10.4049/jimmunol.0902587
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IL-22 Produced by Human NK Cells Inhibits Growth of Mycobacterium tuberculosis by Enhancing Phagolysosomal Fusion1

Rohan Dhiman,*{dagger} Mohanalaxmi Indramohan,*{dagger} Peter F. Barnes,*{dagger}{ddagger} Ramesh C. Nayak,§ Padmaja Paidipally,*{dagger} L. Vijaya Mohan Rao,§ and Ramakrishna Vankayalapati2*{dagger}

*Center for Pulmonary and Infectious Disease Control, Departments of {dagger}Microbiology and Immunology and {ddagger}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 {gamma}-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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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.

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

3 Abbreviations used in this paper: siRNA, small interfering RNA.






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