Immunosuppressive functions of hepatic myeloid-derived suppressor cells of normal mice and in a murine model of chronic hepatitis B virus

Chen, S.; Akbar, Sk. Md. Fazle; Abe, Masanori; Hiasa, Yoichi; Onji, Morikazu

doi:10.1111/j.1365-2249.2011.04445.x

Cited by 92 publications

(96 citation statements)

References 25 publications

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“…Therefore, the precise role of MDSCs in chronic virus infection and their associations with outcome remain elusive. In this study, to our knowledge for the first time, we identified an increase for a population of CD14 + cells that have low or no expression of HLA-DR in a cohort of CHB patients, in agreement with previous studies in HBV transgenic mice and HIV patients (21,22,34). Interestingly, the presence of MDSCs was associated with increased PD-1 expression, suggesting that the immunosuppressive phenotype of MDSCs in CHB patients is CD14 + HLA-DR 2/low PD-1 + .…”

Section: Discussionsupporting

confidence: 77%

Myeloid-Derived Suppressor Cells Regulate Immune Response in Patients with Chronic Hepatitis B Virus Infection through PD-1–Induced IL-10

Huang

Zhang

Yan

et al. 2014

The Journal of Immunology

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Although myeloid-derived suppressor cells (MDSCs) are well known for their immunosuppressive function in several pathological conditions, the role of MDSCs in hepatitis B virus infection remains obscure. In this study, we investigated the frequency and function of MDSCs in the peripheral blood and liver of 91 chronic hepatitis B (CHB) patients. A higher percentage of MDSCs, defined as CD14+HLA-DR−/low, was detected in peripheral blood of CHB patients than that of the healthy controls. Moreover, high expression of programmed death 1 (PD-1) and secretion of IL-10 in this population were determined. The frequency of MDSCs was positively correlated with serum viral load, but it was negatively correlated with liver inflammatory injury. These cells were also abundant in liver tissue of CHB patients and were related to necroinflammatory activity. Furthermore, we found that these cells could suppress hepatitis B virus–specific CD8+ T cell response, including reduced proliferation and IFN-γ production, and inhibit degranulation of CD8+ T cells, including reduced production of granzyme B and perforin. Importantly, PD-1–induced IL-10 production by MDSCs was responsible for the suppressive activity. To our knowledge, for the first time our study proved that CD14+HLA-DR–/lowPD-1+ MDSCs in CHB patients contribute to an inadequate immune response against the virus and lead to chronic infection, which represents a potential target for therapeutic intervention.

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Section: Discussionsupporting

confidence: 77%

Myeloid-Derived Suppressor Cells Regulate Immune Response in Patients with Chronic Hepatitis B Virus Infection through PD-1–Induced IL-10

Huang

Zhang

Yan

et al. 2014

The Journal of Immunology

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“…It has been reported that MDSCs of diseased mice have an increased capacity to suppress T-cell proliferation compared with MDSCs of normal mice. 28 This is supported by the finding that MDSCs from healthy controls show decreased expression of immunosuppressive molecules compared with MDSCs from cancer patients. 29 Likewise, in a previous study we showed that arginase-1 is expressed in PBMCs in much larger amounts in lung cancer patients than in healthy controls.…”

Section: Discussionsupporting

confidence: 76%

“…However, in mice, MDSCs are also present in the liver during physiological conditions and are thought to play a pivotal role in maintaining homeostasis. 28 Therefore, the function of MDSCs is probably different in healthy controls and cancer patients. It has been reported that MDSCs of diseased mice have an increased capacity to suppress T-cell proliferation compared with MDSCs of normal mice.…”

Section: Discussionmentioning

confidence: 99%

Immunoglobulin-like transcript 3 is expressed by myeloid-derived suppressor cells and correlates with survival in patients with non-small cell lung cancer

et al. 2015

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Myeloid-derived suppressor cells (MDSCs) play an important role in immune suppression and accumulate under pathologic conditions such as cancer and chronic inflammation. They comprise a heterogeneous population of immature myeloid cells that exert their immunosuppressive function via a variety of mechanisms. Immunoglobulin-like transcript 3 (ILT3) is a receptor containing immunoreceptor tyrosine-based inhibition motifs (ITIMs) that can be expressed on antigen-presenting cells and is an important regulator of dendritic cell tolerance. ILT3 exists in a membrane-bound and a soluble form and can interact with a yet unidentified ligand on T cells and thereby induce T-cell anergy, regulatory T cells, or T suppressor cells. In this study, we analyzed freshly isolated peripheral blood mononuclear cells (PBMCs) of 105 patients with non-small cell lung cancer and 20 healthy controls and demonstrated for the first time that ILT3 is expressed on MDSCs. We show that increased levels of circulating MDSCs correlate with reduced survival. On the basis of ILT3 cell surface expression, an ILT3 low and ILT3 high population of polymorphonuclear (PMN)-MDSCs could be distinguished. Interestingly, in line with the immunosuppressive function of ILT3 on dendritic cells, patients with an increased proportion of PMN-MDSCs and an increased fraction of the ILT3 high subset had a shorter median survival than patients with elevated PMN-MDSC and a smaller ILT3 high fraction. No correlation between the ILT3 high subset and other immune variables was found. ILT3 expressed on MDSCs might reflect a previously unknown mechanism by which this cell population induces immune suppression and could therefore be an attractive target for immune intervention.

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“…Targeting the S1P1R-signaling pathway, FTY720 potentiates MDSC recruitment and function and promotes reciprocal differentiation of Tregs and Th1 cells for protection against hepatic injuries. This is inconsistent with the previously established role for MDSCs in limiting autoimmune hepatic inflammatory injury (45). Our studies reveal a previously unknown feature of MDSC function in liver homeostasis, the reprogramming of T cell differentiation from Th1 cells to iTregs, which represents a novel mechanism of FTY720-mediated protection against immunological hepatic injuries by targeting the S1P receptor-mTOR-signaling pathway.…”

Section: Discussioncontrasting

confidence: 56%

Targeting S1P1 Receptor Protects against Murine Immunological Hepatic Injury through Myeloid-Derived Suppressor Cells

Liu

Wang

et al. 2014

The Journal of Immunology

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Although FTY720 may alter migration and homing of lymphocytes via sphingosine-1-phosphate (S1P) receptors, our recent studies indicated that FTY720 directly controls the differentiation of Th1 cells to regulatory T cells (Tregs) by targeting S1P1. However, the pharmacological function of FTY720 in immunological hepatic injury remains unknown. In this study, the role and regulatory signaling pathway of S1P receptor were investigated using a pharmacological approach in immune-mediated hepatic injury (IMH). In the context of IMH, FTY720 significantly ameliorated mortality and hepatic pathology. In FTY720-treated mice, recruited CD11b+Gr1+ myeloid-derived suppressor cells (MDSCs) mediate protection against IMH and are functional suppressive immune modulators that result in fewer IFN-γ–producing Th1 cells and more Foxp3+ Tregs. In agreement, FTY720-treated MDSCs promote the reciprocal differentiation between Th1 cells and Tregs in vitro and in vivo. Mechanistically, FTY720 treatment induced inducible NO synthase expression and NO production in MDSCs. Pharmacologic inhibition of inducible NO synthase completely eliminates MDSC suppressive function and eradicates their inducible effects on T cell differentiation. Finally, the mTOR inhibitor, rapamycin, photocopies the effects of FTY720 on MDSCs, implicating mTOR as a downstream effector of S1P1 signaling. This study identifies MDSCs as an essential component that provides protection against IMH following FTY720 or rapamycin treatment, validating the S1P1–mTOR signaling axis as a potential therapeutic target in hepatic injury.

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Immunosuppressive functions of hepatic myeloid-derived suppressor cells of normal mice and in a murine model of chronic hepatitis B virus

Cited by 92 publications

References 25 publications

Myeloid-Derived Suppressor Cells Regulate Immune Response in Patients with Chronic Hepatitis B Virus Infection through PD-1–Induced IL-10

Myeloid-Derived Suppressor Cells Regulate Immune Response in Patients with Chronic Hepatitis B Virus Infection through PD-1–Induced IL-10

Immunoglobulin-like transcript 3 is expressed by myeloid-derived suppressor cells and correlates with survival in patients with non-small cell lung cancer

Targeting S1P1 Receptor Protects against Murine Immunological Hepatic Injury through Myeloid-Derived Suppressor Cells

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