title: Cryptococcus gattii is killed by dendritic cells, but evades adaptive immunity by failing to induce dendritic cell maturation.
abstract: During adaptive immunity to pathogens, dendritic cells (DCs) capture, kill, process, and present microbial Ags to T cells. Ag presentation is accompanied by DC maturation driven by appropriate costimulatory signals. However, current understanding of the intricate regulation of these processes remains limited. Cryptococcus gattii, an emerging fungal pathogen in the Pacific Northwest of Canada and the United States, fails to stimulate an effective immune response in otherwise healthy hosts leading to morbidity or death. Because immunity to fungal pathogens requires intact cell-mediated immunity initiated by DCs, we asked whether C. gattii causes dysregulation of DC functions. C. gattii was efficiently bound and internalized by human monocyte-derived DCs, trafficked to late phagolysosomes, and killed. Yet, even with this degree of DC activation, the organism evaded pathways leading to DC maturation. Despite the ability to recognize and kill C. gattii, immature DCs failed to mature; there was no increased expression of MHC class II, CD86, CD83, CD80, and CCR7, or decrease of CD11c and CD32, which resulted in suboptimal T cell responses. Remarkably, no increase in TNF-α was observed in the presence of C. gattii. However, addition of recombinant TNF-α or stimulation that led to TNF-α production restored DC maturation and restored T cell responses. Thus, despite early killing, C. gattii evades DC maturation, providing a potential explanation for its ability to infect immunocompetent individuals. We have also established that DCs retain the ability to recognize and kill C. gattii without triggering TNF-α, suggesting independent or divergent activation pathways among essential DC functions.
authors.affiliation: Department of Microbiology and Infectious Disease, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Shaunna M
authors.initials: SM
authors.lastname: Huston
authors.forename: Shu Shun
authors.initials: SS
authors.lastname: Li
authors.forename: Danuta
authors.initials: D
authors.lastname: Stack
authors.forename: Martina
authors.initials: M
authors.lastname: Timm-McCann
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Jones
authors.forename: Anowara
authors.initials: A
authors.lastname: Islam
authors.forename: Byron M
authors.initials: BM
authors.lastname: Berenger
authors.forename: Richard F
authors.initials: RF
authors.lastname: Xiang
authors.forename: Pina
authors.initials: P
authors.lastname: Colarusso
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Mody
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D003453:Cryptococcosis / Q000276:immunology* / Q000382:microbiology / Q000473:pathology*; D056285:Cryptococcus gattii / Q000254:growth & development / Q000276:immunology* / Q000472:pathogenicity; D003713:Dendritic Cells / Q000276:immunology* / Q000382:microbiology / Q000473:pathology*; D006801:Humans; D057131:Immune Evasion / Q000276:immunology*; D016130:Immunophenotyping; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology
chemical_list: D014409:Tumor Necrosis Factor-alpha