Dendritic cell-mediated protection against cryptococcus neoformans

During pulmonary infection with the opportunistic fungal pathogen Cryptococcus neoformans, dendritic cells (DCs) are critical for protection. We show for the first time that plasmacytoid DCs (pDCs) contribute to protective immunity against C. neoformans An increase in pDC infiltration to the lungs was observed in mice infected with a C. neoformans strain that induces protective immunity (H99γ), compared to mice given wild type C. neoformans, which appears to be signal transducer and activator of transcription 1 (STAT1) dependent. We also show that pDCs have direct anti-cryptococcal activity via reactive oxygen species. pDC anti-cryptococcal activity is independent of opsonization, but appears to require the C-type lectin receptor Dectin-3, a receptor not previously investigated in cryptococcal infections. Human pDCs can inhibit cryptococcal growth in a mechanism similar to murine pDCs, demonstrating the therapeutic potential of these unique cells. Recent studies have demonstrated that conventional DCs (cDCs) have the ability to activate to a pro-inflammatory DC1 or an anti-inflammatory DC2 phenotype. The roles of DC1 or DC2 cDCs during cryptococcal infection are unknown. We observed an increase in the number of cDCs that traffic into the lungs of mice infected with H99γ compared to mice given wild type C. neoformans cDCs isolated from the lungs of mice infected with H99γ show an increase in DC1 associated genes and markers while cDCs isolated from the lungs of WT infected mice displayed an increase in DC2 associated genes and markers. cDCs isolated from protectively immunized mice that were challenged with WT yeast exhibited a mixed DC1/DC2 response, suggesting that some cDCs display a memory-like response and polarize to a DC1 phenotype whereas the other cDCs respond like a WT infection. cDCs isolated from the protectively immunized mice and subsequently simulated with Cryptococcus produced pro-inflammatory Th1 cytokines, which was dampened by treatment with methyltransferase inhibitors. Altogether, our studies suggest that DCs (cDCs and pDCs) play a role in the protective immune response against C. neoformans