Monocytic Myeloid-Derived Suppressor Cells in Chronic Infections

Abstract

Heterogeneous populations of myeloid regulatory cells (MRC), including monocytes, macrophages, dendritic cells, and neutrophils, are found in cancer and infectious diseases. The inflammatory environment in solid tumors as well as infectious foci with persistent pathogens promotes the development and recruitment of MRC. These cells help to resolve inflammation and establish host immune homeostasis by restricting T lymphocyte function, inducing regulatory T cells and releasing immune suppressive cytokines and enzyme products. Monocytic MRC, also termed monocytic myeloid-derived suppressor cells (M-MDSC), are bona fide phagocytes, capable of pathogen internalization and persistence, while exerting localized suppressive activity. Here, we summarize molecular pathways controlling M-MDSC genesis and functions in microbial-induced non-resolved inflammation and immunopathology. We focus on the roles of M-MDSC in infections, including opportunistic extracellular bacteria and fungi as well as persistent intracellular pathogens, such as mycobacteria and certain viruses. Better understanding of M-MDSC biology in chronic infections and their role in antimicrobial immunity, will advance development of novel, more effective and broad-range anti-infective therapies.

Keywords: Staphylococcus; human immunodeficiency virus; infection; inflammation; myeloid-derived suppressor cells; tuberculosis; viral hepatitis.

Figure 1

Genesis of monocytic myeloid-derived suppressor cells (M-MDSC) during infectious diseases. Hypothetical models were derived from ex vivo results, correlative studies in animal models as well as clinical observations. Immature myeloid cells (IMC) are generated either in bone marrow or in spleen as a consequence of emergency myelopoiesis. Growth factors, cytokines, and lipids promote progression of hematopoietic stem cells (HSC) toward common myeloid progenitor (CMP) development and subsequent IMC genesis. Combination of cytokines as well as direct stimulation of selected microbial receptors by various microorganisms may activate or reprogram circulating monocytes toward M-MDSC. M-MDSC are recruited in various organs where they exert suppressive function and modulate manifestations and outcome of the disease. Abbreviations: AdV, adenovirus; AKT, protein kinase B; ERK, extracellular signal-regulated kinase; GM-CSF, granulocyte-macrophage colony stimulating factor; gp120, glycoprotein 120; HBV, hepatitis B virus; HBVsAg, HBV soluble antigen; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IAV, influenza A virus; IFN-γ, interferon gamma; IL-6, interleukin 6; LPS, lipopolysaccharide; LP-BM5, virus murine acquired-immune deficiency syndrome (AIDS); MHV-68, murine herpesvirus 68; MyD88, myeloid differentiation primary response gene 88; NF-κB, nuclear factor “kappa-light-chain-enhancer” of activated B-cells; PI3K, phosphatidylinositide 3-kinase; PGE2, prostaglandin E2; STAT, signal transducer and activator of transcription; SIV, simian immunodeficiency virus; tat, trans-activator of transcription; TLR, toll-like receptor.

Figure 2

Features of monocytic myeloid-derived suppressor cells (M-MDSC) and their interactions with immune cells during infection. M-MDSC express membrane-bound inhibitory receptors and upregulate enzymatic pathways [inducible nitric oxide synthase (iNOS), ARG1, COX2, IDO] conferring suppressive activity toward multiple myeloid and lymphoid cell subsets. The key function of M-MDSC is suppression of T-cell immunity. M-MDSC restrict proliferation and release of cytokines by effector CD4 and CD8 lymphocytes and induce apoptotic cell death in these cells. In addition, these myeloid regulatory cells induce regulatory T and B cells, while limiting antibody release and proliferation of conventional B cells. M-MDSC alter activity of NK cells and antigen-presenting cells (APCs) and induce polarization of macrophages toward a regulatory phenotype. Color-coded arrows indicate induction/activation (green) or suppression (red), and molecules employed by M-MDSC for such effects are highlighted. Size- and color-coded arrows indicate gradient fluxes for selected essential amino acids. Boxes indicate cellular functions or pathways modulated by M-MDSC. Abbreviations: ADAM17, ADAM metallopeptidase domain 17; ARG1, arginase 1; CD, cluster of differentiation; COX2, cyclooxygenase 2; DC, dendritic cell; IDO1, indoleamine dioxygenase 1; IFN-γ, interferon gamma; IL-10, interleukin 10; iNOS, inducible nitric oxide synthase; Kyn, kynurenine; l-Arg, l-arginine; l-Cys, l-cysteine; MΦ, macrophage; NK, natural killer cell; NKGD2, killer cell lectin like receptor K1; NOX1, NADPH oxidase 1; PGE2, prostaglandin E2, PD-L1, programmed-death ligand 1; RNS, reactive nitrogen species; ROS, reactive oxygen species; STAT, signal transducer and activator of transcription; TGF-β, transforming growth factor beta; Trp, tryptophan; VISTA, V-domain Ig suppressor of T-cell Activation.