Human fibrocytic myeloid‐derived suppressor cells express IDO and promote tolerance via Treg‐cell expansion

Abstract

By restraining T-cell activation and promoting Treg-cell expansion, myeloid-derived suppressor cells (MDSCs) and tolerogenic DCs can control self-reactive and antigraft effector T cells in autoimmunity and transplantation.Their therapeutic use and characterization, however, is limited by their scarce availability in the peripheral blood of tumor-free donors. In the present study, we describe and characterize a novel population of human myeloid suppressor cells, named fibrocytic MDSC, which are differentiated from umbilical cord blood precursors by 4-day culture with FDA-approved cytokines (recombinant human-GM-CSF and recombinant human-G-CSF). This MDSC subset, characterized by the expression of MDSC-, DC-, and fibrocyte-associated markers, promotes Treg-cell expansion and induces normoglycemia in a xenogeneic mouse model of Type 1 diabetes. In order to exert their protolerogenic function, fibrocytic MDSCs require direct contact with activated T cells, which leads to the production and secretion of IDO. This new myeloid subset may have an important role in the in vitro and in vivo production of Treg cells for the treatment of autoimmune diseases, and in either the prevention or control of allograft rejection. Functionally, tDC can promote Treg-cell expansion, clonal deletion of T cells, and inhibition of memory T-cell response [16]. Hence, MDSCs are still considered a heterogeneous population that includes both immature precursors and more differentiated macrophage-, dendritic-, granulocytic-, or monocytic-like subsets [17][18][19]. Because of the tolerogenic and suppressive properties of MDSCs and tDCs, a growing interest exists on these populations as cellular tools to restore tolerance in autoimmunity, or to prevent graft rejection in transplantation [20], but the definition of a viable and sufficient source of these cells in humans is still needed. KeywordsIn the present study, we differentiated a subset of human MDSCs that express fibrocyte and DC markers from the umbilical cord blood (UCB) of healthy newborn babies. These cells have potent tolerogenic activity and induce selective expansion of Treg cells via the production of IDO upon contact with activated T cells. Results UCB-derived myeloid suppressive population is generated by G-CSF and GM-CSF inductionDue to UCB clinical availability and its high content of immunoregulatory elements, we tested our protocol for the differentiation of mouse and human BM-derived MDSC [21], to obtain a similar cell population from UCB. Briefly, 2-day-old UCB units were purified and cultured in the presence of recombinant human-GM-CSF and recombinant human-G-CSF, and characterized by multicolor FACS analysis, before and after 4 days of culture. Culture in the presence of both cytokines results in the differentiation of a population of myeloid cells with a particular phenotype (Fig. 1A) that co express: (i) markers that define MDSC in different human malignances such as CD33 and IL-4Rα (colon cancer and melanoma [22]), CD11b (renal [23], breast [24], and head and neck carc...

Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected

“…In fact, some studies have shown that fibrocytes represent a unique subset of MDSCs that differentiate from M-MDSCs in the presence of IL-4. These cells can suppress immune responses through expression of indoleamine oxidase (IDO) and expansion of Tregs (86,87).…”

The emerging role of myeloid-derived suppressor cells in lung diseases

“…Recent studies suggest that Gr1 + myeloid-derived monocytic cells and MDSCs can transdifferentiate into extracellular matrix (collagen type I)-producing fibrocytes, a mechanism involving CD4 + T-cells, IL-2, IL-4, IFN-γ and TNF, GM-CSF/G-CSF, Kruppel-like factor 4 and fibroblast-specific protein 1 [68][69][70]. Fibrocytic MDSCs were found to interact with activated T-cells in a cell contact dependent manner, resulting in the production of IDO and leading to Treg expansion [69].…”

“…Fibrocytic MDSCs were found to interact with activated T-cells in a cell contact dependent manner, resulting in the production of IDO and leading to Treg expansion [69]. Fibrocytes can migrate into the tumour stroma microenvironment and further differentiate into myofibroblasts and promote tumorigenesis [71,72] as well as metastasis [73].…”

Exacerbation of Autoimmune Thyroiditis by CTLA-4 Blockade: A Role for IFNγ-Induced Indoleamine 2, 3-Dioxygenase

“…Here, one would predict that increased IDO expression is beneficial to the host because it suppresses a key pathogenic cell type in autoimmunity: the antigen-specific effector T cell (35). Moreover, a beneficial effect has been shown after administration of a subset of myeloid cells that increase IDO synthesis, leading to expansion of regulatory T cells and correction of hyperglycemia in a mouse model of type 1 diabetes (36). Similarly, NOD-H2 h4 mice developed an attenuated form of thyroiditis when injected with an adenovirus expressing IDO directly into the thyroid gland one day before and four weeks after the beginning of iodine supplementation in the drinking water (37).…”