Phenotype, development, and biological function of myeloid-derived suppressor cells

Abstract

CD11b⁺Gr-1⁺ myeloid-derived suppressor cells (MDSCs) are an important population of innate regulatory cells mainly comprising monocytic MDSCs (M-MDSCs) with a phenotype of CD11b⁺Ly6G^-Ly6C^high and granulocytic MDSCs (G-MDSCs) with a phenotype of CD11b⁺Ly6G⁺Ly6C^low in mice. They play crucial roles in the pathogenesis of cancers, chronic infections, autoimmune diseases, and transplantation. Various extracellular factors such as lipopolysaccharide (LPS), macrophage colony-stimulating factor (M-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), stem cell factor (SCF), interleukin (IL)-6, interferon gamma (IFNγ), IL-1β, vascular endothelial growth factor (VEGF), Hsp72, IL-13, C5a, and prostaglandin E2 (PGE2) can induce MDSC differentiation, whereas IL-4 and all-trans-retinoic acid can inhibit this process. For the intracellular signals, signal transducer and activator of transcription (STAT) family members, C/EBPβ and cyclooxigenase-2 (COX-2) promote MDSC function, whereas interferon regulatory factor-8 (IRF-8) and Smad3 downregulate MDSC activity. The immunosuppressive function of MDSCs is mediated through various effector molecules, primarily cellular metabolism-related molecules such as nitric oxide (NO), arginase, reactive oxygen species (ROS), transforming growth factor β (TGFβ), IL-10, indoleamine 2,3-dioxygenase (IDO), heme oxygenase-1 (HO-1), carbon monoxide (CO), and PGE2. In this article, we will summarize the molecules involved in the induction and function of MDSCs as well as the regulatory pathways of MDSCs.

Keywords: immune modulation; immune tolerance; immunosuppression; innate cells; myeloid-derived suppressor cells.

Figure 1.

Molecules involved in the induction and function of MDSCs. Numerous factors can induce the development and differentiation of MDSCs. These factors include, but are not limited to, lipopolysaccharide (LPS); macrophage-colony stimulating factor (M-CSF); granulocyte macrophage-colony stimulating factor (GM-CSF); stem cell factor (SCF); interleukin 6 (IL-6); interferon gamma (IFNγ); IL-1β; vascular endothelial growth factor (VEGF); Hsp72; IL-13; C5a; and prostaglandin E 2 (PGE2). IL-4/GM-CSF and all-trans-retinoic acid may inhibit the development of MDSCs. Some of the intracellular molecules involved in MDSC function include Stat3, COX-2, hypoxia-inducible factor 1a (HIF-1α), C/EBPβ, inducible nitric oxide synthase (iNOS), arginase, heme oxygenase 1 (HO-1), and IDO. The known effector molecules of MDSCs include: (1) arginase-1, which induces arginine deprivation and causes CD3ζ nitrosylation and downmodulation; (2) iNOS, which induces nitric oxide (NO) production and leads to T-cell apoptosis and inhibition of T-cell proliferation; (3) NOX2, which inhibits T-cell proliferation through reactive oxygen species (ROS) production, CD3ζ and major histocompatibility complex (MHC)-I nitration; (4) the enzyme HO-1, which leads to inhibition of T-cell proliferation through carbon monoxide (CO) production; (5) MDSCs that prevent antigen-presenting cells (APCs) from providing sufficient cysteine to T cells for glutathione (GSH) production, thus inhibiting T-cell proliferation; (6) membrane-bound TGFβ1, which promotes NK cell anergy and induced regulatory T cells (iTreg); (7) IL-10 promotes Th2 deviation and type 2 macrophage polarization; (8) ADAM metallopeptidase domain 17 (ADAM17) activity leads to cleavage of L-selectin (CD62L) on T cells resulting in inhibition of T-cell homing to lymph nodes and sites of inflammation.

Figure 2.

Molecules that mediate MDSC immunosuppressive ability. MDSCs suppress T cells, NK cells, and the differentiation of myeloid cells via different mechanisms. The classic mechanism for MDSCs to inhibit T-cell proliferation and promoting Treg cell expansion is through arginine deprivation, nutrition depletion, or high levels of NO production to inhibit T-cell function. Upregulation of HIF1-α expression under hypoxic conditions can enhance the inhibitory function of MDSCs via the mentioned pathways. Signal transducer and activator of transcription 3 (Stat3), a key factor in MDSCs, can increase ROS production by MDSCs, which inhibits T-cell proliferation and myeloid differentiation. In addition, infected cells or tumors can produce GM-CSF and IL-6, both of which increase C/EBPβ expression and promote MDSC differentiation. Furthermore, PGE2, IL-6, and M-CSF from inflammatory cells can produce IDO, IL-10, and CO via regulating COX2 and HO-1 to prevent T-cell proliferation and myeloid cell differentiation. However, MDSC-mediated NK cell inhibition occurs by TGFβ or downregulation of the NK–cell-activating receptor, Nkp30. IL, interleukin; M-CSF, macrophage colony-stimulating factor; PGE2, prostaglandin E2; COX-2, cyclooxygenase-2; IDO, indoleamine 2,3-dioxygenase; HIF-1α, hypoxia-inducible factor-1α; NOS, nitric oxide synthase; Stat3, signal transducer and activator of transcription 3; ROS, reactive oxygen species; TGFβ, transforming growth factor-β.