Abstract
Tuberculosis (TB) has tremendous public health relevance. It most frequently affects the lung and is characterized by the development of unique tissue lesions, termed granulomas. These lesions encompass various immune populations, with macrophages being most extensively investigated. Myeloid derived suppressor cells (MDSCs) have been recently identified in TB patients, both in the circulation and at the site of infection, however their interactions with Mycobacterium tuberculosis (Mtb) and their impact on granulomas remain undefined. We generated human monocytic MDSCs and observed that their suppressive capacities are retained upon Mtb infection. We employed an in vitro granuloma model, which mimics human TB lesions to some extent, with the aim of analyzing the roles of MDSCs within granulomas. MDSCs altered the structure of and affected bacterial containment within granuloma-like structures. These effects were partly controlled through highly abundant secreted IL-10. Compared to macrophages, MDSCs activated primarily the NF-κB and MAPK pathways and the latter largely contributed to the release of IL-10 and replication of bacteria within in vitro generated granulomas. Moreover, MDSCs upregulated PD-L1 and suppressed proliferation of lymphocytes, albeit with negligible effects on Mtb replication. Further comprehensive characterization of MDSCs in TB will contribute to a better understanding of disease pathogenesis and facilitate the design of novel immune-based interventions for this deadly infection.
Highlights
Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB), a disease that accounted for 1.7 million deaths in 2016 [1]
These co-culture studies suggest that the suppressive property of Myeloid derived suppressor cells (MDSCs) is retained upon mycobacterial infection independent of key virulence factors, such as those encoded by region of difference 1 (RD1), which is absent in BCG
Using in vitro differentiated MDSCs we demonstrated that this monocytic subset readily phagocytosed Mtb, albeit allowing reduced bacillary replication in monocultures, abundantly released IL-10 and employed this cytokine for promoting growth of Mtb within IVGLSs
Summary
Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB), a disease that accounted for 1.7 million deaths in 2016 [1]. Caseous granulomas which develop at the site of Mtb infection are considered a hallmark of pulmonary TB [2]. M-MDSC Support M. tuberculosis Replication in Granulomas as by foreign bodies [3]. The cellular composition of TB granulomas may vary with disease stage. Trajectories and the fate of granulomas are determined by a plethora of secreted factors, such as cytokines and eicosanoids, which are locally produced by immune cells [6], in situ changes in cellular composition, as well as viability, replicative and metabolic features of the mycobacteria [7, 8]. Presence of selected immune cell subsets, their location, as well as their propensity to produce soluble mediators control stability of granulomas and TB progression
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