Granulocytic myeloid derived suppressor cells expand in human pregnancy and modulate T‐cell responses

Immune tolerance toward the semiallogeneic fetus plays a crucial role in the maintenance of pregnancy. Myeloid‐derived suppressor cells (MDSCs) are innate immune cells characterized by their ability to modulate T‐cell responses. Recently, we showed that MDSCs accumulate in cord blood of healthy newborns, yet their role in materno–fetal tolerance remained elusive. In the present study, we demonstrate that MDSCs with a granulocytic phenotype (GR‐MDSCs) are highly increased in the peripheral blood of healthy pregnant women during all stages of pregnancy compared with nonpregnant controls, whereas numbers of monocytic MDSCs were unchanged. GR‐MDSCs expressed the effector enzymes arginase‐I and iNOS, produced high amounts of ROS and efficiently suppressed T‐cell proliferation. After parturition, GR‐MDSCs decreased within a few days. In combination, our results show that GR‐MDSCs expand in normal human pregnancy and may indicate a role for MDSCs in materno–fetal tolerance.     

Myeloid‐derived suppressor cells in obstetrical and gynecological diseases

Myeloid‐derived suppressor cells (MDSCs) are a heterogeneous group of myeloid‐origin cells which have immunosuppressive activities in several conditions, such as cancer and inflammation. Recent research has also associated MDSCs with numerous obstetrical and gynecological diseases. During pregnancy, MDSCs accumulate to ensure maternal‐fetal immune tolerance, whereas they are decreased in patients who suffer from early miscarriage or pre‐eclampsia. While the etiology of endometriosis is still unknown, abnormal accumulation of MDSCs in the peripheral blood and peritoneal fluid, alongside an increased level of reactive oxygen species (ROS), has been observed in these patients, which is central to the cellular immune regulations by MDSCs. Additionally, the regulation of MDSCs observed in tumours is also applicable to gynecologic neoplasms, including ovarian cancer and cervical cancer. More recently, emerging evidence has shown that there are high levels of MDSCs in premature ovarian failure (POF) and in vitro fertilization (IVF), but the underlying mechanisms are unknown. In this review, the generation and mechanisms of MDSCs are summarized. In particular, the modulation of these cells in immune‐related obstetrical and gynecological diseases is discussed, including potential treatment options targeting MDSCs.     

Myeloid‐derived suppressor cells mediate tolerance induction in autoimmune disease

In multiple sclerosis (MS) T cells aberrantly recognize self‐peptides of the myelin sheath and attack the central nervous system (CNS). Antigen‐specific peptide immunotherapy, which aims to restore tolerance while avoiding the use of non‐specific immunosuppressive drugs, is a promising approach to combat autoimmune disease, but the cellular mechanisms behind successful therapy remain poorly understood. Myeloid‐derived suppressor cells (MDSCs) have been studied intensively in the field of cancer and to a lesser extent in autoimmunity. Because of their suppressive effect on the immune system in cancer, we hypothesized that the development of MDSCs and their interaction with CD4⁺ T cells could be beneficial for antigen‐specific immunotherapy. Hence, changes in the quantity, phenotype and function of MDSCs during tolerance induction in our model of MS were evaluated. We reveal, for the first time, an involvement of a subset of MDSCs, known as polymorphonuclear (PMN)‐MDSCs, in the process of tolerance induction. PMN‐MDSCs were shown to adopt a more suppressive phenotype during peptide immunotherapy and inhibit CD4⁺ T‐cell proliferation in a cell‐contact‐dependent manner, mediated by arginase‐1. Moreover, increased numbers of tolerogenic PMN‐MDSCs, such as observed over the course of peptide immunotherapy, were demonstrated to provide protection from disease in a model of experimental autoimmune encephalomyelitis.     

Myeloid derived suppressor cells in breast cancer: A novel therapeutic target?

The relationship of the immune system and tumour cells is complex; although recognised that the immune system can protect the host against tumour development, the immune system also facilitates tumour progression through immune suppression. Pro-inflammatory mediators associated with chronic inflammation are responsible for the expansion and activation of myeloid derived suppressor cells (MDSCs); a heterogeneous group of cells that originates from myeloid progenitor cells but does not complete the final stages of differentiation. A causal relationship between chronic inflammation and tumour progression relies on the accumulation and maintenance of MDSCs as its linchpin; responsible for immunosuppression through the down-regulation of anti-tumour responses. MDSCs cause immunosuppression through a number of mechanisms; inhibiting the proliferation of CD4⁺ and CD8⁺ T cells, blocking natural killer cell activation and limiting dendritic cell maturation and function. As well as using various mechanisms to inhibit adaptive and immune responses, MDSCs also have non-immunological functions that aid tumour spread; including directly promoting tumour proliferation and metastasis by having an important role in tumour angiogenesis, secretion of matrix metalloproteinases and induction of epithelial-mesenchymal transition. Breast cancer is the most common cancer among women in the United Kingdom with 44540 new cases of invasive carcinoma in 2013 and results in the second highest cancer mortality rate in women, with 11600 deaths in 2012. Considering this, the need for novel therapeutic interventions is higher than ever. This review summarises the rationale for the targeting of MDSCs in breast cancer as a realistic avenue to increase survival from breast cancer.     

Antigen specificity of immune suppression by myeloid-derived suppressor cells

Among the mechanisms set in motion by the tumor to escape the control of the immune system, MDSCs play a central role in inducing tolerance to a variety of anti-tumor effectors, including T lymphocytes. It has been demonstrated that MDSCs expand in tumor-bearing mice and in cancer patients, leading to an impairment of T cell reactivity against the tumor. However, as the presence of MDSCs is not correlated with a general immune suppression, it was advanced that a mechanism regulating the specificity of MDSC inhibition must be present. In this article, we review the literature showing that MDSCs exert their immune-suppressive function on Ag-specific T cell responses but at times, also on mitogen-activated T lymphocytes, therefore bypassing the Ag dependency. We propose that the features of MDSC-mediated immune suppression might be influenced not only by the specific microenvironment in which MDSCs expand and by the tumor characteristics but also by the levels of activation of the target lymphocytes.     

The immunosuppressive tumour network: myeloid‐derived suppressor cells,regulatory T cells and natural killer T cells

Myeloid‐derived suppressor cells (MDSC) and regulatory T (Treg) cells are major components of the immune suppressive tumour microenvironment (TME). Both cell types expand systematically in preclinical tumour models and promote T‐cell dysfunction that in turn favours tumour progression. Clinical reports show a positive correlation between elevated levels of both suppressors and tumour burden. Recent studies further revealed that MDSCs can modulate the de novo development and induction of Treg cells. The overlapping target cell population of Treg cells and MDSCs is indicative for the importance and flexibility of immune suppression under pathological conditions. It also suggests the existence of common pathways that can be used for clinical interventions aiming to manipulate the TME. Elimination or reprogramming of the immune suppressive TME is one of the major current challenges in immunotherapy of cancer. Interestingly, recent findings suggest that natural killer T (NKT) cells can acquire the ability to convert immunosuppressive MDSCs into immunity‐promoting antigen‐presenting cells. Here we will review the cross‐talk between MDSCs and other immune cells, focusing on Treg cells and NKT cells. We will consider its impact on basic and applied cancer research and discuss how targeting MDSCs may pave the way for future immunocombination therapies.     

IL-33 Neutralization Suppresses Lupus Disease in Lupus-Prone Mice

IL-33 is a new member of the IL-1 family that plays a role in inflammation. In this study, we evaluated the potential of IL-33 inhibition as a treatment for systemic lupus erythematosus (SLE) using the lupus-prone model MRL/lpr mice and the underlying mechanisms of action. We treated mice with anti-mouse IL-33 antibody (anti-IL-33Ab) via intraperitoneal injection every other day from week 14 until week 20 for 6 weeks. A control group received the same amount of IgG control. Renal damage and mouse survival were compared. Cytokines, antibodies, immune complex, Tregs, myeloid-derived suppressor cells (MDSCs), and Th17 cells were also analyzed. Correlations between serum IL-33 and SLE disease activity index in human SLE were also investigated. MRL/lpr mice treated with anti-IL-33Ab showed reduced proteinuria and reduced serum anti-dsDNA levels. Nephritis, immune complex deposits, and the circulating antibodies and immune complex besides the mortality were significantly reduced by anti-IL-33Ab. Anti-IL-33Ab remarkably increased Tregs and MDSCs and reduced the Th17 cells and IL-1β, IL-6, and IL-17 levels in MRL/lpr mice. These results suggest that IL-33 inhibition may inhibit SLE via expansion of Tregs and MDSCs and inhibition of Th17 cells and proinflammatory responses, indicating that blockade of IL-33 has a protective effect on SLE.     

Phenotypic Plasticity of MDSC in Cancers

Myeloid-derived suppressor cells (MDSCs) were initially reported as suppressor of the adaptive immune responses against cancer and other diseases. However, emerging evidence suggest that MDSCs may also support anti-tumor immune responses under certain conditions or may inhibit tumor growth. In the present mini-review, we suggest that such opposing functions of MDSCs are due to phenotypic plasticity of the myeloid cells, allowing them to produce a diverse form of morphology, physiological state, and function in response to environmental conditions. Therefore, they can be manipulated by means of immune modulators to overcome their immune suppressive function.     

Neutrophilic myeloid‐derived suppressor cells in cord blood modulate innate and adaptive immune responses

Neonates show an impaired anti‐microbial host defence, but the underlying immune mechanisms are not understood fully. Myeloid‐derived suppressor cells (MDSCs) represent an innate immune cell subset characterized by their capacity to suppress T cell immunity. In this study we demonstrate that a distinct MDSC subset with a neutrophilic/granulocytic phenotype (Gr‐MDSCs) is highly increased in cord blood compared to peripheral blood of children and adults. Functionally, cord blood isolated Gr‐MDSCs suppressed T cell proliferation efficiently as well as T helper type 1 (Th1), Th2 and Th17 cytokine secretion. Beyond T cells, cord blood Gr‐MDSCs controlled natural killer (NK) cell cytotoxicity in a cell contact‐dependent manner. These studies establish neutrophilic Gr‐MDSCs as a novel immunosuppressive cell subset that controls innate (NK) and adaptive (T cell) immune responses in neonates. Increased MDSC activity in cord blood might serve as key fetomaternal immunosuppressive mechanism impairing neonatal host defence. Gr‐MDSCs in cord blood might therefore represent a therapeutic target in neonatal infections.     

Polyunsaturated fatty acids promote the expansion of myeloid‐derived suppressor cells by activating the JAK/STAT3 pathway

Polyunsaturated fatty acids (PUFAs) exert immunosuppressive effects that could prove beneficial in clinical therapies for certain autoimmune and inflammatory disorders. However, the mechanism of PUFA‐mediated immunosuppression is far from understood. Here, we provide evidence that PUFAs enhance the accumulation of myeloid‐derived suppressor cells (MDSCs), a negative immune regulator. PUFA‐induced MDSCs have a more potent suppressive effect on T‐cell responses than do control MDSCs. These observations were found both in cultured mouse bone marrow cells in vitro and in vivo in mice fed diets enriched in PUFAs. The enhanced suppressive activity of MDSCs by PUFAs administration was coupled with a dramatic induction of nicotinamide adenine dinucleo‐ tide phosphate oxidase subunit p47^phox and was dependent on reactive oxygen species (ROS) production. Mechanistic studies revealed that PUFAs mediate its effects through JAK‐STAT3 signaling. Inhibition of STAT3 phosphorylation by JAK inhibitor JSI‐124 almost completely abrogated the effects of PUFAs on MDSCs. Moreover, the effects of PUFAs on MDSCs and the underlying mechanisms were confirmed in tumor‐bearing mice. In summary, this study sheds new light on the immune modulatory role of PUFAs, and demonstrates that MDSCs expansion may mediate the effects of PUFAs on the immune system.     

Molecular mechanisms regulating myeloid-derived suppressor cell differentiation and function

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.     

Two SHIPs passing in the middle of the immune system

Immunity requires a complex, multiscale system of molecules, cells, and cytokines. In this issue of the European Journal of Immunology, Collazo et al. [Eur. J. Immunol. 2012. 42: 1785-1796] provide evidence that links the lipid phosphatase SHIP1 with the coordination of interactions between regulatory T (Treg) cells and myeloid-derived suppressor cells (MDSCs). Using conditional knockouts of SHIP1 in either the myeloid or T-cell-lineage of mice, the authors show that the regulated development of Treg cells is controlled directly by cell-intrinsic SHIP1, and indirectly by extrinsic SHIP1 control of an unknown myeloid cell. Regulation of MDSCs is also determined by SHIP1 in an extrinsic manner, again via an as-yet-unknown myeloid cell. Furthermore, this extrinsic control of Treg cells and MDSCs is mediated in part by increased production of G-CSF, a growth factor critical for the production of neutrophils, in SHIP1-deficient mice. Thus, a physiologically important implication of this report is the collaboration between the innate and adaptive immune systems in fine tuning of Treg cells as discussed in this commentary.     

Myeloid-derived suppressor cells: the dark knight or the joker in viral infections?

Myeloid derived suppressor cells (MDSCs) are immature cells of myeloid origin, frequently found in tumor microenvironments and in the blood of cancer patients. In recent years, MDSCs have also been found in non-cancer settings, including a number of viral infections. The evasion of host immunity employed by viruses to establish viral persistence strikingly parallels mechanisms of tumor escape, prompting investigations into the generation and function of MDSCs in chronic viral infections. Importantly, analogous to the tumor microenvironment, MDSCs effectively suppress antiviral host immunity by limiting the function of several immune cells including T cells, natural killer cells, and antigen-presenting cells. In this article, we review studies on the mechanisms of MDSC generation, accumulation, and survival in an effort to understand their emergent importance in viral infections. We include a growing list of viral infections in which MDSCs have been reported. Finally, we discuss how MDSCs might play a role in establishing chronic viral infections and identify potential therapeutics that target MDSCs.     

Impaired antigen‐specific lymphocyte priming in mice after Toll‐like receptor 4 activation via induction of monocytic myeloid‐derived suppressor cells

In sepsis, the pathology involves a shift from a proinflammatory state toward an immunosuppressive phase. We previously showed that an agonistic anti‐TLR4 antibody induced long‐term endotoxin tolerance and suppressed antigen‐specific secondary IgG production when primed prior to immunization with antigen. These findings led us to speculate that TLR4‐induced innate tolerance due to primary infection causes an immunosuppressive pathology in sepsis. Therefore, the mechanism underlying impaired antigen‐specific humoral immunity by the TLR4 antibody was investigated. We showed, in a mouse model, that primary antigen‐specific IgG responses were impaired in TLR4 antibody‐induced tolerized mice, which was the result of reduced numbers of antigen‐specific GC B cells and plasma cells. Ovalbumin‐specific CD4 and CD8 T‐cell responses were impaired in TLR4 antibody‐injected OT‐I and ‐II transgenic mice ex vivo. Adoptive transfer studies demonstrated suppression of OVA‐specific CD4 and CD8 T‐cell responses by the TLR4 antibody in vivo. The TLR4 antibody induced Gr1⁺CD11b⁺ myeloid‐derived suppressor cell (MDSC) expansion with suppression of T‐cell activation. Monocytic MDSCs were more suppressive and exhibited higher expression of PD‐L1 and inducible nitric oxidase compared with granulocytic MDSCs. In conclusion, immune tolerance conferred by TLR4 activation induces the expansion of monocytic MDSCs, which impairs antigen‐specific T‐cell priming and IgG production.     

Suppression of T cells by myeloid-derived suppressor cells in cancer

Myeloid-derived suppressor cells (MDSCs) are a population of immature myeloid cells defined by their immunosuppression. Elevated levels of certain soluble cytokines in tumor microenvironment, such as IL-6 and IL-10, contribute to the recruitment and accumulation of tumor-associated MDSCs. In turn, MDSCs secret IL-6 and IL-10 and form a positive self-feedback to promote self-expansion. MDSCs also release other soluble cytokines such as TGF-β and chemokines to exert their suppressive function by induction of regulatory T cells. Exhaustion of some amino acids by MDSCs with many secretory enzymes or membrane transporters as well as their metabolites leads to blockage of T cells development. The interaction of membrane molecules on MDSCs and T cells leads inactivation and apoptosis of T cells. There may be one or some dominant mechanism(s) by which MDSCs impair the immune system in different tumor microenvironment. Thus, it is important to identify the subpopulations of MDSCs and clarify the dominant mechanism(s) through which MDSCs inhibit antitumor immunity in order to establish a more individual immunotherapy by eliminating MDSCs-mediated suppression. Currently studies concentrated on therapeutic strategies targeting MDSCs have obtained promising results. However, more studies are needed to demonstrate their clinical safety and efficacy.