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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<jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>. Infectious outcomes in DAP12<jats:sup>\u2212\/\u2212<\/jats:sup>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<jats:sup>\u2212\/\u2212<\/jats:sup>mice. In contrast to WT NK cells, DAP12<jats:sup>\u2212\/\u2212<\/jats:sup>NK cells are able to repress<jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>growth<jats:italic>in vitro<\/jats:italic>. Additionally, DAP12<jats:sup>\u2212\/\u2212<\/jats:sup>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<jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>. These findings suggest that DAP12 acts as a brake on the pulmonary immune response to<jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>by promoting pulmonary eosinophilia and by inhibiting the activation and antifungal activities of effector cells, including NK cells and macrophages.<\/jats:p>","DOI":"10.1128\/iai.00222-16","type":"journal-article","created":{"date-parts":[[2016,4,12]],"date-time":"2016-04-12T03:23:49Z","timestamp":1460431429000},"page":"1879-1886","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":12,"title":["DAP12 Inhibits Pulmonary Immune Responses to Cryptococcus neoformans"],"prefix":"10.1128","volume":"84","author":[{"given":"Lena J.","family":"Heung","sequence":"first","affiliation":[{"name":"Infectious Diseases Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, 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