Prospects for dendritic cell vaccination against fungal infections in hematopoietic transplantation.

Dendritic cells (DCs) are uniquely able to initiate and control the immune response to fungi. DCs function at three levels in the manipulation of the immune response to these pathogens. First, they mount an immediate or innate response to them, for example, by producing inflammatory mediators upon capture and phagocytosis; second, through these preceding innate functions, they decode the fungus-associated information and translate it in qualitatively different Th responses, and third, they are key in containing and dampening inflammatory responses by tolerization through the induction of regulatory T cells (Treg). DCs sense fungi in a morphotype-specific manner, through the engagement of distinct recognition receptors ultimately affecting cytokine production and costimulation. Both myeloid and plasmacytoid murine and human DCs phagocytose fungi and undergo functional maturation in response to them. However, their activation program for cytokine production was different, being IL-12 mainly produced by myeloid DCs and IL-12, IL-10 and IFN-alpha mainly produced by plasmacytoid DCs. This resulted in a distinct ability for T cell priming, being Th1, Th2, and Treg differently activated by the different DC subsets. The ability of fungus-pulsed DCs to prime for Th1 and Th2 cell activation upon adoptive transfer in vivo correlated with the occurrence of resistance and susceptibility to the infections, respectively. Antifungal protective immunity was also induced upon adoptive transfer of DCs transfected with fungal RNA. The efficacy was restricted to DCs transfected with RNA from yeasts or conidia but not with RNA from fungal hyphae. The effect was fungus-specific, as no cross-protection was observed upon adoptive transfer of DCs pulsed with either fungal species. The infusion of fungus-pulsed or RNA-transfected DCs accelerated the recovery of functional antifungal Th1 responses in mice with allogeneic hematopoietic stem cell transplantation (HSCT) and affected the outcome of the infections. As the ability of phagocytose fungi was defective in peripheral DCs from patients with HSCT, soon after the transplant, our findings suggest that the adoptive transfer of DCs may restore immunocompetence in HSCT by contributing to the educational program of T cells. Thus, the remarkable functional plasticity of DCs in response to fungi can be exploited for the deliberate targeting of cells and pathways of cell-mediated immunity in response to fungal vaccines.