Molecular mechanisms regulating myeloid-derived suppressor cell differentiation and function

Abstract

Myeloid-derived suppressor cells (MDSCs) are one of the main cell populations responsible for regulating immune responses. MDSCs accumulate during tumor progression, autoimmunity, chronic infection and other pathological conditions, and can potently suppress T cell function. Recent studies have demonstrated the ability of MDSCs to modulate the activity of NK and myeloid cells and have implicated MDSCs in the induction of regulatory T cells. Here, we discuss recent findings that describe the molecular mechanisms that regulate the expansion and function of MDSCs, as well as recent attempts to use MDSCs in cell therapy for different pathologic conditions.

Figure 1. Potential models of MDSC accumulation

Schematic description of the models of MDSC accumulation that require either one or two signals. HPC – hematopoietic progenitor cells. IMC – immature myeloid cells that have phenotype similar to MDSC but lacking immune suppressive activity

Figure 2. Schematics of possible signaling pathways involved in MDSC expansion

Various cytokines produced by tumors or bone marrow stroma in response to chronic infections or inflammation activate several signal transduction pathways that result in activation of Stat3, Stat5. Stat3 regulates transcription of subunits of Nox2 that results in increased production of ROS, as well as up-regulation of a number of anti-apoptotic proteins and possibly CEBPβ that, in turn, up-regulate c-myc. All together these proteins contribute to proliferation and survival of immature myeloid cells and prevent their differentiation to mature cells. This manifests in expansion of cells with the phenotype of MDSC.

Figure 3. Schematics of possible signaling pathways involved in MDSC activation

Bacterial and viral products, as well as cytokines released by activated T cells or myeloid cells induce activation of Stat1, Stat6 and TLR signaling. Stat1 and Stat6 act directly and TLR signaling via MyD88 and NF-κB to up-regulate proteins directly involved in the immune suppressive activity of MDSC.