title: Leishmania-infected macrophages are targets of NK cell-derived cytokines but not of NK cell cytotoxicity.
abstract: Natural killer (NK) cells are important components of a protective immune response against intracellular pathogens such as Leishmania parasites, which reside within myeloid cells. Previous in vivo studies in murine cutaneous or visceral leishmaniasis showed that NK cells are activated by conventional dendritic cells in a Toll-like receptor 9-, interleukin-12 (IL-12)-, and IL-18-dependent manner during the early phase of infection and help to restrict the tissue parasite burden by unknown mechanisms. Here, we tested whether NK cells contribute to the control of Leishmania infections by lysing or by activating infected host cells. Coculture experiments revealed that activated NK cells from poly(I:C)-treated mice readily killed tumor target cells, whereas Leishmania infantum- or L. major-infected macrophages or dendritic cells remained viable. Infection with Leishmania did not significantly alter the expression of NK cell-activating molecules (retinoic acid early transcript alpha [Rae-1α], mouse UL16-binding protein-like transcript 1 [MULT-1], CD48) or inhibitory molecules (major histocompatibility complex [MHC] class I, nonclassical MHC class 1b molecule Qa-1) on the surface of myeloid cells, which offers an explanation for their protection from NK cell cytotoxicity. Consistent with these in vitro data, in vivo cytotoxicity assays revealed poor cytolytic activity of NK cells against adoptively transferred infected wild-type macrophages, whereas MHC class I-deficient macrophages were efficiently eliminated. NK cells activated by IL-12 and IL-18 stimulated macrophages to kill intracellular Leishmania in a cell contact-independent but gamma interferon-, tumor necrosis factor-, and inducible nitric oxide synthase-dependent manner. We conclude that Leishmania parasites, unlike viruses, do not render infected myeloid cells susceptible to the cytotoxicity of NK cells. Instead, soluble products of NK cells trigger the leishmanicidal activity of macrophages.
authors.affiliation: Mikrobiologisches Institut-Klinische Mikrobiologie, Immunologie und Hygiene, Friedrich-Alexander-Universität Erlangen-Nürnberg, and Universitätsklinikum Erlangen, Erlangen, Germany .
authors.forename: Chittappen K
authors.initials: CK
authors.lastname: Prajeeth
authors.forename: Simone
authors.initials: S
authors.lastname: Haeberlein
authors.forename: Heidi
authors.initials: H
authors.lastname: Sebald
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schleicher
authors.forename: Christian
authors.initials: C
authors.lastname: Bogdan
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D000071178:CD48 Antigen; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000235:genetics; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D018664:Interleukin-12 / Q000096:biosynthesis / Q000276:immunology; D020382:Interleukin-18 / Q000096:biosynthesis / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D007891:Leishmania / Q000276:immunology*; D007896:Leishmaniasis / Q000276:immunology; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology / Q000469:parasitology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology; D048069:Tumor Necrosis Factors / Q000276:immunology / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D000071178:CD48 Antigen; D002352:Carrier Proteins; C000604066:Cd48 protein, mouse; D015395:Histocompatibility Antigens Class I; D020382:Interleukin-18; D008565:Membrane Proteins; C491219:Raet1a protein, mouse; D048069:Tumor Necrosis Factors; C468260:UL16 binding protein 1, mouse; D018664:Interleukin-12; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; D011070:Poly I-C