By | June 17, 2021

PU.1 suppresses Th2 cytokine expression via silencing of GATA3 transcription in dendritic cells. and costimulatory substances corresponded with a reduced capacity for trophic form-loaded dendritic cells to stimulate CD4+ T cell proliferation and polarization. These data are consistent with the delayed innate and adaptive responses previously observed in immunocompetent mice inoculated with trophic forms compared to responses in mice inoculated with a mixture of trophic forms and cysts. We propose that trophic forms broadly inhibit the ability of dendritic cells to fulfill their role as antigen-presenting cells. species are opportunistic fungal pathogens that cause severe pneumonia in immunocompromised hosts, including AIDS patients and patients undergoing immunosuppressive therapies. Clearance of organisms is dependent around the generation of effective CD4+ T cell responses (1,C3). Failure to clear organisms leads to severe immune-mediated alveolar damage (4). While improvements in antiviral therapies have reduced the incidence of pneumonia (PcP) in HIV-infected individuals and other at-risk populations, the mortality rate for patients with Dovitinib (TKI-258) PcP has not improved (5). Additional studies are required to inform novel approaches to reduce morbidity and mortality due to pneumonia. species have a biphasic life cycle consisting of trophic forms and cysts. Trophic forms are single-nucleated organisms typically found in clusters surrounded by a biofilm-like material consisting of a conglomeration of DNA, -glucan, and other sugars (6). Cysts are ascus-like structures that consist of multiple nuclei surrounded by a fungal cell wall consisting of -1,3-glucan and -1,6-glucan (7,C9). Trophic forms do not express -glucan and do not form a cell wall (8). Dendritic cells are the principal antigen-presenting cells in the lung. However, their role in initiating the adaptive response to has been understudied. Previous work has exhibited that dendritic cells activated by cell wall-derived -glucan increase the expression of costimulatory molecules and drive Th1 polarization (10). The mechanism for dendritic cell recognition of trophic forms, which do not express -glucan, is unknown. Both stages express surface glycoproteins and mannoproteins that may serve as pathogen-associated molecular patterns (PAMPs) that could be recognized by receptors on host cells (7,C9). Intriguingly, neither life form expresses the classical fungal components ergosterol, chitin, or -glucan (10, 11). We have previously reported that the life cycle stages of have opposing effects around the immune response (11). The immune response to contamination with trophic forms alone was less robust than the response to contamination with a physiologically normal mixture of Dovitinib (TKI-258) cysts and trophic forms. Contamination with trophic forms alone resulted in reduced numbers of CD11c+ innate immune cells in the lungs, as well as reduced recruitment of activated CD4+ and CD8+ T cells, compared to contamination with a normal mixture of trophic forms and cysts. trophic forms hinder the ability of dendritic cells to serve in their essential role as stimulators of CD4+ T cell responses by reducing the capacity of dendritic cells to produce proinflammatory cytokines, present antigen, and express costimulatory molecules. Treatment of dendritic cells with trophic forms induced a less robust pattern of expression of immunity-related Dovitinib (TKI-258) genes than treatment with a mixture of trophic forms and cysts. In addition, treatment with trophic forms Rabbit Polyclonal to MAN1B1 reduced the ability of dendritic cells to increase surface expression of major histocompatibility complex (MHC) Dovitinib (TKI-258) class II and CD40 in response to stimulation with mixed organisms or zymosan. These defects in the expression of MHC class II and costimulatory molecules corresponded with a reduced capacity for trophic form-loaded dendritic cells to stimulate CD4+ T cell proliferation and polarization. RESULTS trophic forms induce a suppressive pattern of gene expression in dendritic cells. trophic forms suppress the production of proinflammatory cytokines by dendritic cells stimulated with multiple PAMPs (11). These PAMPs are recognized by a range of pattern recognition receptors that mediate diverse signaling pathways within the cell, including, in the case of IL-1, inflammasome activation. These data suggest that trophic forms have a broadly suppressive effect on dendritic.