Abstract
Myeloid-derived suppressor cells (MDSCs) regulate T cell immunity, and this population is a new therapeutic target for immune regulation. A previous study showed that transforming growth factor-β (TGF-β) is involved in controlling MDSC differentiation and immunoregulatory function in vivo. However, the direct effect of TGF-β on MDSCs with various cytokines has not previously been tested. Thus, we examined the effect of various cytokine combinations with TGF-β on MDSCs derived from bone marrow cells. The data show that different cytokine combinations affect the differentiation and immunosuppressive functions of MDSCs in different ways. In the presence of TGF-β, interleukin-6 (IL-6) was the most potent enhancer of MDSC function, whereas granulocyte colony-stimulating factors (G-CSF) was the most potent in the absence of TGF-β. In addition, IL-4 maintained MDSCs in an immature state with an increased expression of arginase 1 (Arg1). However, regardless of the cytokine combinations, TGF-β increased expansion of the monocytic MDSC (Mo-MDSC) population, expression of immunosuppressive molecules by MDSCs, and the ability of MDSCs to suppress CD4+ T cell proliferation. Thus, although different cytokine combinations affected the MDSCs in different ways, TGF-β directly affects monocytic-MDSCs (Mo-MDSCs) expansion and MDSCs functions.
Highlights
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous cell population of myeloid-derived cells comprising immature myeloid cells [1]
We demonstrated that transforming growth factor-β (TGF-β) can generate subpopulations of MDSCs with increased expression of immunosuppressive factors such as inducible nitric oxide synthase (iNOS), TGF-β, IL-10, and arginase 1 (Arg1) [23]
GM-Colony-stimulating factors (CSFs) was added to all cytokine combinations because it is essential for MDSC differentiation [24]
Summary
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous cell population of myeloid-derived cells comprising immature myeloid cells (i.e., immature macrophages, granulocytes, dendritic cells, and other myeloid cells in the early stages of differentiation) [1]. MDSCs have immunosuppressive effects; murine MDSCs are commonly defined by expression of CD11b and Gr-1 and are present in low numbers in the spleen and blood of tumor-free mice [2]. Murine MDSCs are characterized according to two epitopes of Gr-1, Ly-6G, and Ly-6C, which are detected by specific antibodies [3]. These epitopes allow separation of MDSCs into two different subpopulations: granulocytic-MDSCs (Gr-MDSCs; CD11b+Ly-6GhighLy-6Clow) and monocytic-MDSCs (Mo-MDSCs; CD11b+Ly-6GdimLy-6Chigh) [4]. Mo-MDSCs secrete transforming growth factor-β (TGF-β) and interleukin-10 (IL-10), which have direct immunosuppressive effects and induce regulatory T cells, which suppress tumor-specific T cell responses [7]
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