Activation of murine invariant NKT cells promotes susceptibility to candidiasis by IL‐10 induced modulation of phagocyte antifungal activity

• Published in: European journal of immunology 2016-07, Vol.46 (7), p.1691-1703
• Main Authors: Haraguchi, Norihiro, Kikuchi, Norihiro, Morishima, Yuko, Matsuyama, Masashi, Sakurai, Hirofumi, Shibuya, Akira, Shibuya, Kazuko, Taniguchi, Masaru, Ishii, Yukio
• Format: Article
• Language: English
• Subjects: Adoptive Transfer; Animals; Candida - immunology; Candida albicans; Candida albicans - immunology; Candidia; Candidiasis; Candidiasis - genetics; Candidiasis - immunology; Candidiasis - metabolism; Candidiasis - microbiology; Cytokines - biosynthesis; Cytokines - metabolism; Disease Models, Animal; Disease Resistance - genetics; Disease Resistance - immunology; Disease Susceptibility - immunology; Host-Pathogen Interactions - genetics; Host-Pathogen Interactions - immunology; IL‐10; Infections; Inflammasome; Inflammation Mediators - metabolism; iNKT cells; Interleukin-10 - metabolism; Macrophages; Macrophages, Peritoneal - immunology; Macrophages, Peritoneal - metabolism; Male; Mice; Mice, Knockout; Mortality; Natural Killer T-Cells - immunology; Natural Killer T-Cells - metabolism; Phagocytes - immunology; Phagocytes - metabolism; Phagocytes - microbiology; Phagocytes - pathology; Phagocytosis - genetics; Phagocytosis - immunology; Receptors, Antigen, T-Cell, alpha-beta - genetics; Rodents
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201545987

Invariant NKT (iNKT) cells play an important role in a variety of antimicrobial immune responses due to their ability to produce high levels of immune‐modulating cytokines. Here, we investigated the role of iNKT cells in host defense against candidiasis using Jα18‐deficient mice (Jα18−/−), which lack iNKT cells. Jα18−/− mice were more resistant to the development of lethal candidiasis than wild‐type (WT) mice. In contrast, treatment of WT mice with the iNKT cell activating ligand α‐galactosylceramide markedly enhanced their mortality after infection with Candida albicans. Serum IL‐10 levels were significantly elevated in WT mice in response to infection with C. albicans. Futhermore, IL‐10 production increased after in vitro coculture of peritoneal macrophages with iNKT cells and C. albicans. The numbers of peritoneal macrophages, the production of IL‐1β and IL‐18, and caspase‐1 activity were also significantly elevated in Jα18−/− mice after infection with C. albicans. The adoptive transfer of iNKT cells or exogenous administration of IL‐10 into Jα18−/− reversed susceptibility to candidiasis to the level of WT mice. These results suggest that activation of iNKT cells increases the initial severity of C. albicans infection, most likely mediated by IL‐10 induced modulation of macrophage antifungal activity. The putative mechanisms for increase in susceptibility to Candidia infections by iNKT cells. Macrophages stimulated with C. albicans might activate iNKT cells by producing IL‐12 and IL‐18; then activated iNKT cells might negatively regulate the anticandidal activities of macrophages and neutrophils by mediating IL‐10.