Myeloid-derived suppressor cells are increased in frequency but not maximally suppressive in peripheral blood of Type 1 Diabetes Mellitus patients

Type 1 Diabetes Mellitus (T1D) results from the destruction of insulin-producing beta cells in the pancreas by autoreactive T cells. Myeloid derived suppressor cells (MDSCs) are a recently identified immune cell subset that down-regulate T cells. Whether defects in MDSC numbers or function may contribute to T1D pathogenesis is not known. We report here that MDSCs are unexpectedly enriched in peripheral blood of both mice and patients with autoimmune diabetes. Peripheral blood MDSCs from T1D patients suppressed T cell proliferation in a contact-dependent manner; however, suppressive function could be enhanced with in vitro cytokine induction. These findings suggest that native T1D MDSCs are not maximally suppressive and that strategies to promote MDSC suppressive function may be effective in preventing or treating T1D.     

Phenotypically resembling myeloid derived suppressor cells are increased in children with HIV and exposed/infected with Mycobacterium tuberculosis

Increased disease susceptibility during early life has been linked to immune immaturity, regulatory T‐cell/TH2 immune biasing and hyporesponsiveness. The contribution of myeloid derived suppressor cells (MDSCs) remains uninvestigated. Here, we assessed peripheral MDSC in HIV‐infected and ‐uninfected children with tuberculosis (TB) disease before, during and after TB treatment, along with matched household contacts (HHCs), HIV‐exposed, ‐infected and ‐uninfected children without recent TB exposure. Serum analytes and enzymes associated with MDSC accumulation/activation/function were measured by colorimetric‐ and fluorescence arrays. Peripheral frequencies of cells phenotypically resembling MDSCs were significantly increased in HIV‐exposed uninfected (HEU) and M.tb‐infected children, but peaked in children with TB disease and remained high following treatment. MDSC in HIV‐infected (HI) children were similar to unexposed uninfected controls; however, HAART‐mediated MDSC restoration to control levels could not be disregarded. Increased MDSC frequencies in HHC coincided with enhanced indoleamine‐pyrrole‐2,3‐dioxygenase (IDO), whereas increased MDSC in TB cases were linked to heightened IDO and arginase‐1. Increased MDSC were paralleled by reduced plasma IP‐10 and thrombospondin‐2 levels in HEU and significantly increased plasma IL‐6 in HI HHC. Current investigations into MDSC‐targeted treatment strategies, together with functional analyses of MDSCs, could endorse these cells as novel innate immune regulatory mechanism of infant HIV/TB susceptibility.     

MDSC subtypes and CD39 expression on CD8+ T cells predict the efficacy of anti-PD-1 immunotherapy in patients with advanced NSCLC

The major suppressive immune cells in tumor sites are myeloid derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and Treg cells, and the major roles of these suppressive immune cells include hindering T-cell activities and supporting tumor progression and survival. In this study, we analyzed the pattern of circulating MDSC subtypes in patients with non-small cell lung cancer (NSCLC) whether those suppressive immune cells hinder T-cell activities leading to poor clinical outcomes. First, we verified PMN-MDSCs, monocytic-MDSCs (M-MDSCs), and Treg cells increased according to the stages of NSCLC, and MDSCs effectively suppressed T-cell activities and induced T-cell exhaustion. The analysis of NSCLC patients treated with anti-PD-1 immunotherapy demonstrated that low PMN-MDSCs, M-MDSCs, and CD39⁺CD8⁺ T cells as an individual and all together were associated with longer progression free survival and overall survival, suggesting PMN-MDSCs, M-MDSCs, and CD39⁺CD8⁺ T cells frequencies in peripheral blood might be useful as potential predictive and prognostic biomarkers.     

Functional characterization of myeloid‐derived suppressor cell subpopulations during the development of experimental arthritis

Recent evidence indicates the existence of subpopulations of myeloid‐derived suppressor cells (MDSCs) with distinct phenotypes and functions. Here, we characterized the role of MDSC subpopulations in the pathogenesis of autoimmune arthritis in a collagen‐induced arthritis (CIA) mouse model. The splenic CD11b⁺Gr‐1⁺ MDSC population expanded in CIA mice, and these cells could be subdivided into polymorphonuclear (PMN) and mononuclear (MO) MDSC subpopulations based on Ly6C and Ly6G expression. During CIA, the proportion of splenic MO‐MDSCs was increased in association with the severity of joint inflammation, while PMN‐MDSCs were decreased. MO‐MDSCs expressed higher levels of surface CD40 and CD86 protein, but lower levels of Il10, Tgfb1, Ccr5, and Cxcr2 mRNA. PMN‐MDSCs exhibited a more potent capacity to suppress polyclonal T‐cell proliferation in vitro, compared with MO‐MDSCs. Moreover, the adoptive transfer of PMN‐MDSCs, but not MO‐MDSCs, decreased joint inflammation, accompanied by reduced levels of serum cytokine secretion and the frequencies of Th1 and Th17 cells in draining lymph nodes. These results suggest that there could be a shift from potently suppressive PMN‐MDSCs to poorly suppressive MO‐MDSCs during the development of experimental arthritis, which might reflect the failure of expanded MDSCs to suppress autoimmune arthritis.     

Liposomal microparticle injection can induce myeloid-derived suppressor cells (MDSC)-like cells in vivo

Context: Myeloid-derived suppressor cells (MDSCs) are a subset of immature myeloid cells that function as immunosuppressive cells in various pathological conditions. Membrane-derived microvesicles are thought to be involved in MDSC induction. Earlier reports have described that injection of considerable amount of liposome into rat can suppress Con A-induced splenic T-cell proliferation. Liposome-internalized cells expressing CD11b/c suppress T-cell proliferation. Nitric oxide (NO) appears to be involved in the suppression. We speculated that, similarly to membrane-derived microvesicles, liposomal microparticles can induce MDSC-like cells in vivo.

Objectives: To confirm our speculation we investigated dose-dependency of the suppressive effect, the effect of liposome on the induction of inducible NO synthase (iNOS), and anti-CD3 antibody-stimulated T-cell proliferation and cytokine production.

Materials and methods: Liposome particles of 250?nm diameter were prepared and suspended in saline. Then, various amounts of liposomal suspension were injected intravenously into rats. After 24?h, rat spleens were removed and concanavalin A (or anti-CD3 antibody) stimulated-splenic T-cell proliferation and the production of iNOS, NO and cytokines were evaluated.

Results: T-cell proliferation was suppressed dose-dependently by liposome injection. The immunosuppressive cell exerts its suppressive activity in a dose-dependent manner. The suppression was eliminated by iNOS inhibitor. iNOS was detected in liposome-loaded splenocytes. Anti-CD3 antibody-stimulated T-cell proliferation was also inhibited. Enhanced production of IL-10 was observed.

Conclusions: Liposomal microparticles can induce MDSC-like cells in vivo. The lipids which comprise liposomes might serve an important role in the induction of MDSCs in vivo.     

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.     

MDSCs drive the process of endometriosis by enhancing angiogenesis and are a new potential therapeutic target

Endometriosis affects women of reproductive age via unclear immunological mechanism(s). Myeloid‐derived suppressor cells (MDSCs) are a heterogeneous group of myeloid cells with potent immunosuppressive and angiogenic properties. Here, we found MDSCs significantly increased in the peripheral blood of patients with endometriosis and in the peritoneal cavity of a mouse model of surgically induced endometriosis. Majority of MDSCs were granulocytic, produced ROS, and arginase, and suppressed T‐cell proliferation. Depletion of MDSCs by antiGr‐1 antibody dramatically suppressed development of endometrial lesions in mice. The chemokines CXCL1, 2, and 5 were expressed at sites of lesion while MDSCs expressed CXCR‐2. These CXC‐chemokines promoted MDSC migration toward endometriotic implants both in vitro and in vivo. Also, CXCR2‐deficient mice show significantly decreased MDSC induction, endometrial lesions, and angiogenesis. Importantly, adoptive transfer of MDSCs into CXCR2‐KO mice restored endometriotic growth and angiogenesis. Together, this study demonstrates that MDSCs play a role in the pathogenesis of endometriosis and identifies a novel CXC‐chemokine and receptor for the recruitment of MDSCs, thereby providing a potential target for endometriosis treatment.     

The roles of myeloid-derived suppressor cells in transplantation

CD11b⁺Gr1⁺ myeloid-derived suppressor cells (MDSCs) are an important regulatory innate cell population and have significant inhibitory effect on T cell-mediated responses. In addition to their negative role in cancer development, MDSCs also exert strong regulatory effects on transplantation and autoimmunity. In many transplantation models, such as bone marrow transplant, renal transplant, heart transplant and skin transplant settings, MDSCs accumulate and have inhibitory effect on graft rejection. However, the inducing factors, detailed phenotype and functional molecular mediators of MDSCs are significantly different in various transplant models. With their strong suppressive activity, MDSCs could become a potential clinical therapy during transplantation tolerance induction and the combination of the MDSCs with other immunoregulatory cells or immunosuppressive drugs is an intriguing protocol in the future. In this review, we will summarize MDSC expansion, activation and induction in different transplantation models and discuss the effects of immunoregulatory cells and immunosuppressive drugs on MDSCs in transplant settings.     

Suppression of Heme Oxygenase-1 by Prostaglandin E2-Protein Kinase A-A-Kinase Anchoring Protein Signaling Is Central for Augmented Cyclooxygenase-2 Expression in Lipopolysaccharide-Stimulated RAW 264.7 Macrophages

Purpose

Prostaglandin (PG) E₂ is an immunomodulatory lipid mediator generated mainly via the cyclooxygenase-2 (COX-2) pathway from arachidonic acid at sites of infection and inflammation. A positive feedback loop of PGE₂ on COX-2 expression is critical for homeostasis during toll-like receptor (TLR)-mediated inflammatory processes. The mechanism of PGE₂-regulated COX-2 expression remains poorly understood. The low-molecular-weight stress protein heme oxygenase-1 (HO-1) contributes to the anti-inflammatory, anti-oxidant and anti-apoptotic response against environmental stress.

Methods

We explored the involvement of HO-1 on PGE₂ regulation of LPS-induced COX-2 expression in RAW 264.7 macrophages.

Results

LPS-induced COX-2 expression in RAW 264.7 macrophages was enhanced by exogenous PGE₂ or cyclic AMP (cAMP) analogue and was suppressed by a COX inhibitor (indomethacin), a protein kinase A (PKA) inhibitor (KT5720), and A kinase anchoring protein (AKAP) disruptors (Ht31 and RIAD). This result suggests that the stimulatory effects of endogenous and exogenous PGE₂ on COX-2 expression are mediated by a cAMP-PKA-AKAP-dependent pathway. The induction of HO-1 was observed in LPS-stimulated RAW 264.7 macrophages. This induction was suppressed by exogenous PGE₂ and enhanced by blockage of the endogenous PGE₂ effect by the PKA inhibitor or AKAP disruptors. In addition, HO-1 induction by the HO activator copper protoporphyrin suppressed LPS-induced COX-2 expression, which was restored by the addition of exogenous PGE₂. The induction of HO-1 inhibited LPS-induced NF-κB p-65 nuclear expression and translocation.

Conclusions

AKAP plays an important role in PGE₂ regulation of COX-2 expression, and the suppression of HO-1 by PGE₂-cAMP-PKA-AKAP signaling helps potentiate the LPS-induced COX-2 expression through a positive feedback loop in RAW 264.7 macrophages.     

Expression of cyclooxygenase-1/-2, microsomal prostaglandin-E synthase-1 and E-prostanoid receptor 2 and regulation of inflammatory mediators by PGE2 in the amoeboid microglia in hypoxic postnatal rats and murine BV-2 cells

This study aimed to investigate the effect of hypoxia on the expression of cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), microsomal prostaglandin-E synthase (mPGES-1), E-prostanoid receptor 2 (EP2) in microglia; and the roles of EP2-cyclic adenosine monophosphate (cAMP) signaling pathway in the prostaglandin E₂ (PGE₂) regulation of inflammatory mediators released by hypoxic BV-2 cells. Immunoexpression of COX-1, COX-2, mPGES-1 and EP2 was localized in the amoeboid microglial cells (AMC), a nascent brain macrophage in the developing brain, as confirmed by double labeling with OX-42 and lectin, specific markers of microglia. AMC emitted a more intense immunofluorescence in hypoxic rats when compared with the matching controls. In postnatal rats subjected to hypoxia, mRNA and protein expression levels of COX-1, COX-2 and mPGES-1 along with tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), inducible nitric-oxide synthase (iNOS) and PGE₂ product in the callosal tissue were significantly increased. The results were shared in the BV-2 cells except for COX-1 mRNA and protein whose levels remained unaltered. Interestingly, treatment with EP2 antagonist AH-6809 resulted in suppression of hypoxia induced EP2, IL-1β and iNOS mRNA and protein expression, TNF-α protein expression and intracellular cAMP level in BV-2 cells. It is suggested that PGE₂ may regulate above inflammatory mediators in the activated microglia via EP2-cAMP signaling pathway in hypoxic conditions.     

Immunomodulatory effects of myeloid-derived suppressor cells in diseases: Role in cancer and infections

Myeloid-derived suppressor cells (MDSCs) are heterogeneous cells capable of abrogating T and B cells responses and have been identified in numerous cancers. As with other regulatory cell populations, they aim to maintain balance between host-defence-associated inflammation and ensuing tissue pathology. MDSC accumulation and/or activation involve several growth factors and cytokines including Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF) and Interleukin (IL)-6 and suppression has been linked to receptors such as IL-4Rα. Other immune pathways, such as Toll-like receptors (TLRs) have also been shown to interfere in MDSC activity adding to the complexity in clarifying their pathways. Monocytic- (Mo-MDSCs) and polymorphonuclear- (PMN-MDSCs) cells are two subsets of MDSCs that have been well characterized and have been shown to function through different mechanisms although both appear to require nitric oxide. In human and murine model settings, MDSCs have been shown to have inhibitory effects on T cell responses during bacterial, parasitic and viral pathologies and an increase of MDSC numbers has been associated with pathological conditions. Interestingly, the environment impacts on MDSC activity and regulatory T cells (Tregs), mast cells and a few cells that may help MDSC in order to regulate immune responses. Since the majority of pioneering data on MDSCs has stemmed from research on malignancies, this review will summarize MDSC biology and function in cancer and highlight current knowledge about these cells during infectious pathologies as well.     

Respective Roles and Interactions of T Lymphocyte and PGE2-Mediated Monocyte Suppressive Activities in Human Newborns and Mothers at the Time of Delivery

ABSTRACT: Recently the concept of a poorly functional humoral immune response in the newborn was proposed. Data have been presented indicating that the impaired newborn B cell maturation, as shown in vitro in a pokeweed mitogen-induced B cell maturation system, is due both to an immaturity of lymphocyte subsets and to an increased suppressive T activity. In the present work, we present evidence that there exists a predominance of a naturally occurring T lymphocyte suppressive activity in the cord blood in that the removal of the suppressive activity by irradiation allows a normal maturation of newborn B cells. Such normal maturation of newborn B cells can also be obtained using mixed cultures of adult T cells and newborn B cells. Newborn suppressor T cells belong to both EAγ(+) and EAγ(—) fractions, and it is not known whether these two groups do or do not belong to different subsets. The PGE₂-dependent monocyte suppressive activity does not play any role in the suppression observed in newborns since newborn monocytes are poorly suppressive and since they produce a smaller amount of PGE₂ than adult monocytes. Some observations suggest, on the contrary, that the suppressive T lymphocytes can regulate the level of the PGE₂-dependent monocyte suppressive activity. It should be noticed that similar observations about T lymphocyte and PGE₂-dependent monocyte suppressive activities have been made at the same time using mothers' cells. These observations suggest the possibility that such changes in B cell immune regulation may result from an interaction between maternal and fetal lymphoid cells.     

Role of myeloid-derived suppressor cells in mouse pre-sensitized cardiac transplant model

Harness of sensitized transplantation remains a clinical challenge particularly in parallel with prolonged cold ischemia time (PCI)-mediated injury. Our present study was to test the role of myeloid-derived suppressor cells (MDSCs) in mouse pre-sensitized transplantation. Our findings revealed that CD11b + Gr1^low MDSC was shown to have strong suppressive activity. MDSCs subsets from the tolerated mice exhibited higher suppressive capacities compared with counterparts from naive (untreated) mice. Depletion of Tregs could not affect splenic CD11b + Gr1^-low MDSC frequency, but increase peripheral and intragraft CD11b + Gr1^-low frequency. Intriguingly, boost of Tregs remarkably caused an increase of CD11b + Gr1^-low frequency in the graft, peripheral blood, and spleen. Furthermore, peripheral CD11b + Gr1^-low cells were massively accumulated at the early stage when allogeneic immune response was enhanced. Taken together, MDSCs could prevent grafts from PCI-mediated injury independent on Tregs in the pre-sensitized transplant recipients. Utilization of MDSC subset particularly CD11b + Gr1^-low might provide a novel insight into improving graft outcome under such clinical scenarios.     

Tumor Necrosis Factor-α Blocks Differentiation and Enhances Suppressive Activity of Immature Myeloid Cells during Chronic Inflammation

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Highlights? TNF-α promotes immunosuppression during chronic inflammation via MDSCs ? TNF-α blocks MDSC maturation by enhancing S100A8/9 and RAGE expression ? TNF-α augments MDSC suppressive activity impairing T and NK cell function ? Etanercept enhances MDSC maturation and reduces their suppressive activity     

A copper chelate selectively triggers apoptosis in myeloid-derived suppressor cells in a drug-resistant tumor model and enhances antitumor immune response

Myeloid-derived suppressor cells (MDSCs), one of the major orchestrators of immunosuppressive network are present in the tumor microenvironment suppress antitumor immunity by subverting Th1 response in tumor site and considered as a great obstacle for advancement of different cancer immunotherapeutic protocols. Till date, various pharmacological approaches have been explored to modulate the suppressive functions of MDSCs in vivo. The present study describes our endeavor to explore a possibility of eradicating MDSCs by the application of a copper chelate, namely copper N-(2-hydroxy acetophenone) glycinate (CuNG), previously found to be a potential immunomodulator that can elicit antitumorogenic Th1 response in doxorubicin-resistant EAC (EAC/Dox) bearing mice. Herein, we demonstrated that CuNG treatment could reduce Gr-1+CD11b+ MDSC accumulation in ascitic fluid and spleen of EAC/Dox tumor model. Furthermore, we found that CuNG mediated reduction in MDSCs is associated with induction of Th1 response and reduction in Treg cells. Moreover, we observed that CuNG could deplete MDSCs by inducing Fas-FasL mediated apoptotic cell death where death receptor Fas expression is enhanced in MDSCs and FasL is provided by activated T cells. However, MDSC expansion from bone marrow cells and their differentiation was not affected by CuNG. Altogether, these findings suggest that the immunomodulatory property of CuNG is attributed to, at least in part, by its selective cytotoxic action on MDSCs. So, this preclinical study unveils a new mechanism of regulating MDSC levels in drug-resistant cancer model and holds promise of translating the findings into clinical settings.     

Role of myeloid-derived suppressor cells in autoimmune disease

Myeloid-derived suppressor cells(MDSCs) represent an important class of immunoregulatory cells that can be activated to suppress T cell functions. These MDSCs can inhibit T cell functions through cell surface interactions and the release of soluble mediators. MDSCs accumulate in the inflamed tissues and lymphoid organs of patients with autoimmune diseases. Much of our knowledge of MDSC function has come from studies involving cancer models, however many recent studies have helped to characterize MDSC involvement in autoimmune diseases. MDSCs are a heterogeneous group of immature myeloid cells with a number of different functions for the suppression of T cell responses. However, we have yet to fully understand their contributions to the development and regulation of autoimmune diseases. A number of studies have described beneficial functions of MDSCs during autoimmune diseases, and thus there appears to be a potential role for MDSCs in the treatment of these diseases. Nevertheless, many questions remain as to the activation, differentiation, and inhibitory functions of MDSCs. This review aims to summarize our current knowledge of MDSC subsets and suppressive functions in tissue-specific autoimmune disorders. We also describe the potential of MDSC-basedcell therapy for the treatment of autoimmune diseases and note some of hurdles facing the implementation of this therapy.