Myeloid-derived suppressor cells: the dark knight or the joker in viral infections?

Abstract

Myeloid derived suppressor cells (MDSCs) are immature cells of myeloid origin, frequently found in tumor microenvironments and in the blood of cancer patients. In recent years, MDSCs have also been found in non-cancer settings, including a number of viral infections. The evasion of host immunity employed by viruses to establish viral persistence strikingly parallels mechanisms of tumor escape, prompting investigations into the generation and function of MDSCs in chronic viral infections. Importantly, analogous to the tumor microenvironment, MDSCs effectively suppress antiviral host immunity by limiting the function of several immune cells including T cells, natural killer cells, and antigen-presenting cells. In this article, we review studies on the mechanisms of MDSC generation, accumulation, and survival in an effort to understand their emergent importance in viral infections. We include a growing list of viral infections in which MDSCs have been reported. Finally, we discuss how MDSCs might play a role in establishing chronic viral infections and identify potential therapeutics that target MDSCs.

Keywords: MDSCs; immunosuppression; viral infection.

Fig. 1. Molecular mechanisms of MDSC action on other immune cells

MDSCs suppress T cells, NK cells, and other myeloid cells via a variety of mechanisms. T cells appear to be mainly suppressed via the production of ROS and RNS or via the depletion of L-arginine. On the other hand, MDSC-mediated inhibition of NK cell responses occur through either membrane-bound TGF-β or downregulation of NK cell activating receptor, NKp30. In contrast to the immunosuppression of MDSCs on NK cell responses, MDSCs are also shown to activate NK cells. In addition, MDSCs act on myeloid cells and affect their differentiation in a ROS-dependent manner. MDSCs, myeloid derived suppressor cells; NK, natural killer cell; ROS, reactive oxygen species; RNS, reactive nitrogen species; TGF-β, transforming growth factor-β.

Fig. 2. Factors involved in the generation and accumulation of MDSCs during viral infection

Upon viral infection, infected cells produce factors, such as IL-6, M-CSF, and PGE2, which prevent the differentiation of MDSCs into mature macrophages and DCs. In particular, PGE2 upregulates COX-2, which increases the production of IDO and IL-10. Additionally, COX-2 acts in a positive feedback loop, generating more PGE2 that propagates immunosuppression. Under hypoxic conditions, upregulation of HIF-1α augments the immunosuppressive effect of MDSCs by increasing NOS and arginase-1. As a key transcription factor involved in the differentiation of MDSCs, STAT3 is also found to play a role in increasing ROS production by MDSCs. Apart from suppressing other immune cells, ROS prevents MDSC differentiation into mature myeloid cells. Lastly, recruitment of MDSCs to the site of infection is directed by TGF-β produced by virally infected cells, which increases the expression of CXCR4 and its ligand CXCL12. MDSCs also produce factors such as IL-1β that increase their accumulation. MDSCs, myeloid derived suppressor cells; IL, interleukin; M-CSF, macrophage-colony stimulating factor; PGE2, prostaglandin E; COX-2, cyclooxygenase-2; IDO, indoleamine 2,3-deoxygenase; HIF-1α, hypoxia-inducible factor-1α; NOS, nitric oxide synthase; STAT3signal transducer and activator of transcription 3; ROS, reactive oxygen species; TGF-β, transforming growth factor-β.