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

Abstract

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 γ-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.

Adaptive immunity to murine skin commensals

“…IL-22 deficiency did not impair the effect of transferred T cells in reducing bacterial transcripts in Rag −/− lymph nodes. Although IL-22 has been reported to inhibit growth of mycobacteria in macrophages (55), there was no effect on mycobacterial infection in IL-22 −/− mice (56). Several common skin conditions are thought to relate to excess reactions of the adaptive immune system in response to commensals.…”

c-Maf–Dependent Growth of Mycobacterium tuberculosis in a CD14hi Subpopulation of Monocyte-Derived Macrophages

“…Monocytes were incubated at 37˚C in a humidified 5% CO 2 atmosphere for 4 d to allow differentiation into macrophages. Some MDMs were uninfected, and others were infected with M. tuberculosis H37Rv at a multiplicity of infection of 2.5:1, as described previously (13). Viability of MDMs was .90% up to 7 d postinfection.…”

rIL-22 as an adjuvant enhances the immunogenicity of rGroEL in mice and its protective efficacy against S. Typhi and S. Typhimurium

“…The beneficial role of IL-22 in host defense has been studied in various infections of the lung and intestine, including Klebsiella pneumonia, 24 C. rodentium, 25 Salmonella Typhimurium 28 and Mycobacterium tuberculosis. 29 Recently, we have reported the immunomodulatory effect of IL-22 expressing plasmid either by co-delivery or by fusion with the GroEL gene of S. Typhi in mice. 30 In continuation of this study, here we report that co-administration of the rIL-22 protein can modulate the rGroEL-mediated immune response against S. Typhi and can augment protection against lethal Salmonella infection in mice.…”