Candida-induced granulocytic myeloid-derived suppressor cells are protective against polymicrobial sepsis

Abstract

Polymicrobial intra-abdominal infections (IAI) can lead to life-threatening sepsis with significant morbidity and mortality, especially when pathogenic fungi are involved. We have employed an established clinically relevant mouse model of fungal/bacterial IAI and shown that immunization with low-virulence Candida species, that is, Candida dubliniensis, can induce responses that protect against sepsis via the suppression of lethal inflammation. This protection is dependent on long-lived Gr-1+ polymorphonuclear leukocytes that display characteristics consistent with myeloid-derived suppressor cells (MDSCs) and trained innate immunity. Here we aimed to functionally and phenotypically characterize these protective Gr-1+ leukocytes. Compared to nonimmunized control mice, we observed increased levels of CD11b+ Gr-1+ cells systemically and locally in the peritoneal cavity of immunized mice. Isolated peritoneal Gr-1+ cells displayed hallmark MDSC phenotypes including increased T-cell suppressor activity and increased MDSC effector activity. Furthermore, we observed increased levels of the anti-inflammatory MDSC cytokine interleukin (IL)-10 in the peritoneal cavity of immunized mice and, in contrast, increased inflammatory responses when Gr-1+ leukocytes were depleted from immunized mice prior to challenge. Flow cytometric analysis revealed that Ly6G+ granulocytic MDSCs (G-MDSCs) were preferentially increased over Ly6C+ monocytic MDSCs (M-MDSCs) in immunized mice. Importantly, G-MDSCs, but not M-MDSCs, as well as IL-10 production, are required for full protection against lethal sepsis. From these data, we conclude that the Gr-1+ leukocytes that protect against polymicrobial sepsis are bona fide MDSCs and hypothesize that the mechanism of MDSC-mediated protection includes abrogation of lethal inflammation by IL-10.