title: Natural killer cell intrinsic toll-like receptor MyD88 signaling contributes to IL-12-dependent IFN-γ production by mice during infection with Toxoplasma gondii.
abstract: Myeloid differentiation factor 88 (MyD88)-dependent IL-12 secretion by dendritic cells is critical for natural killer cell-mediated IFN-γ production and innate resistance to Toxoplasma gondii. Although MyD88(-/-) mice challenged with T. gondii have defective IL-12 responses and succumb to infection, administration of IL-12 to MyD88(-/-) mice fails to prevent acute mortality, suggesting that MyD88 may mediate signals within natural killer cells important for IL-12-dependent IFN-γ production and innate resistance to this parasite. In this study, we found that T. gondii antigens and IL-12 could synergistically trigger IFN-γ secretion by natural killer cells, which was dependent on toll-like receptor-MyD88 signaling. Further analysis showed that p38 mitogen-activated protein kinase, extracellular signal-regulated kinase, c-Jun N-terminal kinase and NF-κB multiple pathways downstream of MyD88 contributed to IFN-γ production by natural killer cells. Moreover, the well-established toll-like receptor agonists, T. gondii profilin (Tgprofilin) and T. gondii heat shock protein 70 (TgHSP70) could evoke a similar IFN-γ secretory response in natural killer cells to that evoked by T. gondii antigens. In vivo adoptive transfer experiments showed that, upon challenge with T. gondii, NOD/SCID-β2 microglobulin null (NOD/SCID-β2m(-/-)) mice injected i.v. with MyD88(-/-) natural killer cells had reduced serum IFN-γ levels and increased splenic tachyzoite burdens compared with those injected i.v. with wild-type natural killer cells. Taken together, these findings demonstrate a critical role for natural killer cell intrinsic toll-like receptor-MyD88 signaling in IL-12-dependent early IFN-γ production and innate resistance to T. gondii.
authors.affiliation: Department of Pathogen Biology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, China; Institute of Pathogenic Microbiology, Jiangsu Provincial Center for Disease Prevention and Control, Key Laboratories of Enteric Pathogenic Microbiology, Ministry of Health, Nanjing, China.
authors.forename: Yiyue
authors.initials: Y
authors.lastname: Ge
authors.affiliation: Department of Pathogen Biology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, China; Department of Parasitology and Microbiology, School of Medicine, Nantong University, Nantong, Jiangsu, China.
authors.forename: Jinling
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Pathogen Biology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Qiu
authors.affiliation: Department of Pathogen Biology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Institute of Pathogenic Microbiology, Jiangsu Provincial Center for Disease Prevention and Control, Key Laboratories of Enteric Pathogenic Microbiology, Ministry of Health, Nanjing, China.
authors.forename: Lunbiao
authors.initials: L
authors.lastname: Cui
authors.affiliation: Institute of Pathogenic Microbiology, Jiangsu Provincial Center for Disease Prevention and Control, Key Laboratories of Enteric Pathogenic Microbiology, Ministry of Health, Nanjing, China.
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Qi
authors.affiliation: Department of Pathogen Biology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, China.
authors.forename: Xinjian
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pathogen Biology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, China.
authors.forename: Jingfan
authors.initials: J
authors.lastname: Qiu
authors.affiliation: Institute of Pathogenic Microbiology, Jiangsu Provincial Center for Disease Prevention and Control, Key Laboratories of Enteric Pathogenic Microbiology, Ministry of Health, Nanjing, China.
authors.forename: Zhiyang
authors.initials: Z
authors.lastname: Shi
authors.affiliation: State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Zhaorong
authors.initials: Z
authors.lastname: Lun
authors.affiliation: Department of Parasitology, Anhui Medical University, Hefei, China.
authors.forename: Jilong
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Pathogen Biology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, China. Electronic address: yongwsh@njmu.edu.cn.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D000953:Antigens, Protozoan / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D053472:Nod Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014122:Toxoplasma; D014124:Toxoplasmosis, Animal / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D000953:Antigens, Protozoan; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D053472:Nod Signaling Adaptor Proteins; D018664:Interleukin-12; D007371:Interferon-gamma; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: IFN-γ; MyD88; NK cells; Toxoplasma gondii