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.

Cryptococcus gattii Infection Dampens Th1 and Th17 Responses by Attenuating Dendritic Cell Function and Pulmonary Chemokine Expression in the Immunocompetent Hosts

“…Our data showing reduced expression levels of MHC-II in lung DCs and pulmonary cytokines IL-12/IL-23, attenuated production of antigen-specific Th1/Th17 cytokines in lung draining lymph nodes, and failure to generate Th1/Th17 cells upon stimulation with C. gattii-treated DCs in vitro indicate that Th1 and Th17 cells, which are critical for the host against fungal infection, are inefficiently developed in response to C. gattii infection. Similar to our findings, human dendritic cells exposed to C. gattii failed to mature and were incompetent to activate T cells (32).…”

Dendritic Cell-Based Immunization Ameliorates Pulmonary Infection with Highly Virulent Cryptococcus gattii

“…Huston et al showed that human DCs derived from CD14 ϩ peripheral blood mononuclear cells (PBMCs) could engulf and kill C. gattii strain R265 but that DCs failed to mature in the presence of C. gattii (38). They also showed that TNF-␣ could restore DC maturation to induce T cell responses in the presence of C. gattii, which suggested the potential of DC-based therapies to improve the outcomes of patients with C. gattii infections.…”

Cryptococcus gattii Infections

“…There are relatively few studies of host cell interactions with C. gattii that provide novel insights into pathogenesis, but a recent publication on the evasion of the adaptive immune response by C. gattii strains R265 and R272 is instructive, as similar evasion has not been demonstrated for C. neoformans (167). This group demonstrated that heat-killed C. gattii is efficiently bound to, and internalized by, human peripheral blood-derived dendritic cells (DCs), trafficked to late phagolysosomes, and killed.…”