Lung-Residing Myeloid-derived Suppressors Display Dual Functionality in Murine Pulmonary Tuberculosis

Rationale: Myeloid cells encompass distinct populations with unique functions during homeostasis and disease. Recently, a novel subset of innate cells, myeloid-derived suppressor cells (MDSCs), has been described in cancer, which suppresses T-cell responses and fosters disease progression. The role of MDSCs in infection is insufficiently addressed. Objectives: To examine the presence and function of MDSCs during experimental pulmonary tuberculosis (TB) and further understand the immunologic consequences of direct interactions between MDSCs and lung bacterial pathogens. Methods: Using cell-based approaches and experimental mouse models for pulmonary TB we characterized MDSCs as novel myeloid populations directly interacting with Mycobacterium tuberculosis (Mtb). Measurements and Main Results: MDSCs readily phagocytosed Mtb, and released proinflammatory (IL-6, IL-1 alpha) and immunomodulatory (IL-10) cytokines while retaining their suppressive capacity. MDSCs were identified at the site of infection in the lung in disease-resistant and -susceptible mice during pulmonary TB. Excessive MDSC accumulation in lungs correlated with elevated surface expression of IL-4R alpha and heightened TB lethality, whereas targeted depletion of MDSCs ameliorated disease. Conclusions: Our data reveal that MDSCs provide a niche for pathogen survival and tailor immunity in TB. These findings suggest MDSCs as amenable targets for host-directed therapies and emphasize them as cellular-immune regulators during chronic inflammatory conditions, including chronic infections and microbial complications of neoplastic disorders.