title: DAP12 Inhibits Pulmonary Immune Responses to Cryptococcus neoformans.
abstract: Cryptococcus neoformans is an opportunistic fungal pathogen that is inhaled into the lungs and can lead to life-threatening meningoencephalitis in immunocompromised patients. Currently, the molecular mechanisms that regulate the mammalian immune response to respiratory cryptococcal challenge remain poorly defined. DAP12, a signaling adapter for multiple pattern recognition receptors in myeloid and natural killer (NK) cells, has been shown to play both activating and inhibitory roles during lung infections by different bacteria and fungi. In this study, we demonstrate that DAP12 plays an important inhibitory role in the immune response to C. neoformans Infectious outcomes in DAP12(-/-) mice, including survival and lung fungal burden, are significantly improved compared to those in C57BL/6 wild-type (WT) mice. We find that eosinophils and macrophages are decreased while NK cells are increased in the lungs of infected DAP12(-/-) mice. In contrast to WT NK cells, DAP12(-/-) NK cells are able to repress C. neoformans growth in vitro Additionally, DAP12(-/-) macrophages are more highly activated than WT macrophages, with increased production of tumor necrosis factor (TNF) and CCL5/RANTES and more efficient uptake and killing of C. neoformans These findings suggest that DAP12 acts as a brake on the pulmonary immune response to C. neoformans by promoting pulmonary eosinophilia and by inhibiting the activation and antifungal activities of effector cells, including NK cells and macrophages.
authors.affiliation: Infectious Diseases Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Lena J
authors.initials: LJ
authors.lastname: Heung
authors.affiliation: Infectious Diseases Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA hohlt@mskcc.org.
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Hohl
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D000818:Animals; D018946:Chemokine CCL5 / Q000235:genetics / Q000276:immunology; D003453:Cryptococcosis / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D003455:Cryptococcus neoformans / Q000254:growth & development / Q000276:immunology / Q000472:pathogenicity*; D004195:Disease Models, Animal; D004804:Eosinophils / Q000276:immunology / Q000382:microbiology; D015966:Gene Expression Regulation, Fungal; D054884:Host-Pathogen Interactions; D007694:Killer Cells, Natural / Q000276:immunology / Q000382:microbiology; D008168:Lung / Q000276:immunology / Q000382:microbiology; D008172:Lung Diseases, Fungal / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D016676:Macrophages, Alveolar / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D061251:Primary Cell Culture; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; D014409:Tumor Necrosis Factor-alpha; C484963:Tyrobp protein, mouse