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.
A B S T R A C TLectins are proteins with a high degree of stereospecificity to recognize various sugar structures and form reversible linkages upon interaction with glyco-conjugate complexes. These are abundantly found in plants, animals and many other species and are known to agglutinate various blood groups of erythrocytes. Further, due to the unique carbohydrate recognition property, lectins have been extensively used in many biological functions that make use of protein-carbohydrate recognition like detection, isolation and characterization of glycoconjugates, histochemistry of cells and tissues, tumor cell recognition and many more. In this review, we have summarized the immunomodulatory effects of plant lectins and their effects against diseases, including antimicrobial action. We found that many plant lectins mediate its microbicidal activity by triggering host immune responses that result in the release of several cytokines followed by activation of effector mechanism. Moreover, certain lectins also enhance the phagocytic activity of macrophages during microbial infections. Lectins along with heat killed microbes can act as vaccine to provide long term protection from deadly microbes. Hence, lectin based therapy can be used as a better substitute to fight microbial diseases efficiently in future.
We previously found that human NK cells lyse Mycobacterium tuberculosis-infected monocytes and alveolar macrophages and upregulate CD8+ T cell responses. We also found that human NK cells produce IL-22, which inhibits intracellular growth of M. tuberculosis, and that NK cells lyse M. tuberculosis-expanded CD4+CD25+FOXP3+ T regulatory cells (Tregs). To determine the role of NK cells during the protective immune response to vaccination in vivo, we studied the NK cell and T cell responses in a mouse model of vaccination with bacillus Calmette-Guérin (BCG), followed by challenge with virulent M. tuberculosis H37Rv. BCG vaccination enhanced the number of IFN-γ–producing and IL-22–producing NK cells. Depletion of NK1.1+ cells at the time of BCG vaccination increased the number of immunosuppressive Tregs (CD4+CD25hi, 95% Foxp3+) after challenge with M. tuberculosis H37Rv, and NK1.1+ cells lysed expanded but not natural Tregs in BCG-vaccinated mice. Depletion of NK1.1+ cells at the time of BCG vaccination also increased the bacillary burden and reduced T cell responses after challenge with M. tuberculosis H37Rv. IL-22 at the time of vaccination reversed these effects and enhanced Ag-specific CD4+ cell responses in BCG-vaccinated mice after challenge with M. tuberculosis H37Rv. Our study provides evidence that NK1.1+ cells and IL-22 contribute to the efficacy of vaccination against microbial challenge.
Previously, we found that interleukin 22 (IL-22) inhibits intracellular growth of Mycobacterium tuberculosis in human monocyte-derived macrophages (MDMs). In the current study, we determined the mechanisms underlying these effects. We found that W7, a phagolysosomal fusion inhibitor, abrogates IL-22-dependent M. tuberculosis growth inhibition in MDMs, suggesting that IL-22 acts through enhanced phagolysosomal fusion. Our microarray analysis indicated that recombinant IL-22 (rIL-22) enhances the expression of an intracellular signaling molecule, calgranulin A. This was confirmed by real-time polymerase chain reaction, Western blot, and confocal microscopy. Calgranulin A small interfering RNA (siRNA) abrogated rIL-22-dependent growth inhibition of M. tuberculosis in MDMs. IL-22 enhanced Rab7 expression and downregulated Rab14 expression of M. tuberculosis-infected MDMs, and these effects were reversed by calgranulin A siRNA. These results suggest that M. tuberculosis growth inhibition by IL-22 depends on calgranulin A and enhanced phagolysosomal fusion, which is associated with increased Rab7 and reduced Rab14 expression.
We previously found that CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) expand in response to Mycobacterium tuberculosis infection in individuals who are healthy tuberculin reactors, but not in tuberculin-negative individuals. We also found that the M. tuberculosis mannose-capped lipoarabinomannan and prostaglandin E2 produced by monocytes are involved in Treg expansion. In this study, we found that Tregs expanded from CD4(+)CCR4(+) cells but not from CCR4(-) cells. However, introduction of CCR4 small interfering RNA (siRNA) into CD4(+) cells only marginally reduced expansion of Tregs. Using siRNA and neutralizing antibodies, we found that expansion of Tregs by M. tuberculosis required expression of programmed death1 (PD-1) and expression of the signaling molecule, cytokine inducible SH2-containing protein (CISH). Anti-PD-1 siRNA inhibited expression of CISH by expanded Tregs. M. tuberculosis-expanded Tregs produced transforming growth factor β and interleukin 10 and reduced the frequency of interferon γ-producing autologous CD8(+) cells. We conclude that M. tuberculosis infection induces development of Tregs from CCR4(+) cells through a process that depends on PD-1and CISH.
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