NFAT-dependent IL-2 and IL-23 produced by DC are key regulators of pathogenic (TH17-mediated lung inflammation)

ABSTRACT: Calcineurin/NFAT/IL-2 signaling pathway is activated in dendritic cells (DC) upon encounter of β glucan, the main component of the fungal cell wall, raising the question about the role of NFAT-regulated genes in DC biology in vivo. To directly assess the function of IL-2 secreted by DC, we analyzed mice lacking of IL-2 in the DC lineage, CD4-expressing cells and with complete deletion of IL-2 in the germ line in a mouse model of pulmonary fungal infection. Here we found that specifically the loss of IL-2 in DC resulted in increased mice mortality upon the fungus Aspergillus fumigatus challenge and expansion of Th17 cells in the lung. We demonstrated that only CD103+DC were able to release IL-2 in acute phase of pulmonary Aspergillosis through the Ca2+-Calcineurin-NFAT signaling. We also found that NFAT mediates IL-23 transcription in lung DC, where IL-2 results essential in restraining the priming of a pathogenic infiltrating IL-17+Sca1+CD90+CD4+ cell with stem cell like properties. Thus, IL-2 and IL-23 secreted by DC in the lung have an antagonistic relationship on the Th17 differentiation program with IL-2 inducing T cell differentiation and IL-23 inducing a stem cell like molecular signature to Th17 cells upon Aspergillus challenge. DC-Il2-/- then confer the Th17 stemness, releasing IL-23 in response to the fungus contributing to the development of a Th17 cell effector population, particularly pathogenic in infection. D1 cells with no treatment, or treatment with different fungal types or antigens at 1, 4 and 6 hours, in triplicate, with the 3 untreated samples at 1hr also including techincal repeats

ORGANISM(S): Mus musculus

SUBMITTER: Michael Poidinger 

PROVIDER: E-GEOD-58590 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress