Myeloid-derived suppressor cells as regulators of the immune system

Abstract

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells of myeloid origin. MDSCs expand during various pathological conditions, including cancer, inflammation and trauma, and are characterized by the increased production of reactive oxygen and nitrogen species, and by arginase 1 activity. Two subsets of MDSCs have been identified based on their morphology and cell-surface expression of specific molecules. The granulocytic subset has a CD11b⁺LY6G⁺LY6C^low phenotype and the monocytic subset has a CD11b⁺LY6G⁻LY6C^hi phenotype. Although both subsets can suppress T cells, their mechanisms of suppression are different. The expansion of MDSCs is promoted by numerous factors that include prostaglandins, stem-cell factor, macrophage colony-stimulating factor, granulocyte/macrophage colony-stimulating factor, interleukin-6 (IL-6) and vascular endothelial growth factor. The expansion of MDSCs in pathological conditions is associated with their activation. The main factors that cause MDSC activation are interferon-γ, ligands for Toll-like receptors, IL-4, IL-13 and transforming growth factor-β. Immunosuppressive functions of MDSCs require direct cell–cell contact and can result in antigen-specific or antigen-non-specific suppression of T-cell responses. Arginase 1, inducible nitric oxide synthase, reactive oxygen species and peroxynitrite are thought to have a role in MDSC-mediated T-cell suppression. Agents that may be effective for targeting MDSCs for therapy include all-trans retinoic acid, amino-bisphosphonates, inhibitors of cyclooxygenase 2 and phosphodiesterase 5, and some chemotherapeutic drugs.