title: IL-33 signaling regulates innate and adaptive immunity to Cryptococcus neoformans.
abstract: Susceptibility to progressive infection with the fungus Cryptococcus neoformans is associated with an allergic pattern of lung inflammation, yet the factors that govern this host response are not clearly understood. Using a clinically relevant mouse model of inhalational infection with virulent C. neoformans H99, we demonstrate a role for IL-33-dependent signaling in host immune defense. Infection of BALB/c mice with 10(4) CFU of C. neoformans H99 caused a time-dependent induction of IL-33 with accumulation of type 2 pulmonary innate lymphoid cells and alternatively activated macrophages in the lungs as well as Th2-polarized CD4(+) T cells in draining lymph nodes. IL-33R subunit T1/ST2-deficient (T1/ST2(-/-)) mice infected with C. neoformans H99 had improved survival with a decreased fungal burden in the lungs, spleen, and brain, compared with wild-type mice. Signaling through T1/ST2 was required for the accumulation and early production of IL-5 and IL-13 by lung type 2 pulmonary innate lymphoid cells. Further analysis of T1/ST2(-/-) mice revealed increased fungicidal exudate macrophages in the lungs and decreased C. neoformans-specific Th2 cells in the mediastinal lymph nodes. T1/ST2 deficiency also diminished goblet cell hyperplasia, mucus hypersecretion, bronchoalveolar lavage eosinophilia, alternative activation of macrophages, and serum IgE. These observations demonstrate that IL-33-dependent signaling contributes to the expansion of innate type 2 immunity and subsequent Th2-biased lung immunopathology that facilitates C. neoformans growth and dissemination.
authors.affiliation: Division of Experimental Medicine, McGill University, Montreal, Quebec H3A 1A3, Canada.
authors.forename: Adam
authors.initials: A
authors.lastname: Flaczyk
authors.forename: Claudia U
authors.initials: CU
authors.lastname: Duerr
authors.forename: Mitra
authors.initials: M
authors.lastname: Shourian
authors.forename: Erin I
authors.initials: EI
authors.lastname: Lafferty
authors.forename: Jörg H
authors.initials: JH
authors.lastname: Fritz
authors.forename: Salman T
authors.initials: ST
authors.lastname: Qureshi
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology*; D000818:Animals; D002469:Cell Separation; D003453:Cryptococcosis / Q000276:immunology* / Q000378:metabolism; D003455:Cryptococcus neoformans; D004195:Disease Models, Animal; D005434:Flow Cytometry; D007113:Immunity, Innate / Q000276:immunology*; D000067596:Interleukin-33; D007378:Interleukins / Q000276:immunology* / Q000378:metabolism; D008172:Lung Diseases, Fungal / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*
chemical_list: C506535:Il33 protein, mouse; D000067596:Interleukin-33; D007378:Interleukins