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beyond reason
신이시여! 감사합니다.
오늘부로 인체의 면역시스템에 대한 큰 그림을 이해하고 깊은 탐구에 들어갈 수 있게 되었습니다.
신의 사랑을 동반한 인류의 지혜에 깊은 존경과 감사를 보냅니다
Abstract |
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that expand during cancer, inflammation and infection, and that have a remarkable ability to suppress T-cell responses. These cells constitute a unique component of the immune system that regulates immune responses in healthy individuals and in the context of various diseases. In this Review, we discuss the origin, mechanisms of expansion and suppressive functions of MDSCs, as well as the potential to target these cells for therapeutic benefit.
Figure 1 | The origin of mDSCs. a | Immature myeloid cells (IMCs) are part of the normal process of myelopoiesis, which takes place in the bone marrow and is controlled by a complex network of soluble factors, including cytokines (such as granulocyte/macrophage colony-stimulating factor (GM-CSF), macrophage CSF (M-CSF), stem-cell factor (SCF), interleukin-3 (IL-3) and FMS-related tyrosine kinase 3 (FLT3)) and cell-expressed molecules (such as Notch; not shown). Haematopoietic stem cells differentiate into common myeloid progenitor cells and then into IMCs. b | Normally, IMCs migrate to different peripheral organs, where they differentiate into macrophages, dendritic cells or granulocytes. However, factors that are produced during acute or chronic infections, trauma or sepsis, and in the tumour microenvironment promote the accumulation of IMCs at these sites, prevent their differentiation and induce their activation. These cells exhibit immunosuppressive functions and are therefore known as myeloid-derived suppressor cells (MDSCs). MDSCs also accumulate in peripheral lymphoid organs in response to tumour-derived factors. They can also differentiate into tumour-associated macrophages (TAMs) within the tumour microenvironment; the phenotype and function of TAMs is distinct from that of MDSCs. TLR, Toll-like receptor.
Figure 2 | Signalling pathways involved in the expansion of mDSCs. The accumulation of myeloid-derived suppressor cells (MDSCs) is regulated by several factors that are released by tumour cells, tumour stromal cells, activated T cells and macrophages, apoptotic tumour cells, bacterial and viral agents, and by pathogen-infected cells. These factors trigger several different signalling pathways in MDSCs that mainly involve the signal transducer and activator of transcription (STAT) family of transcription factors. STAT3 regulates the expansion of MDSCs by stimulating myelopoiesis and inhibiting myeloid-cell differentiation, and it promotes MDSC survival by inducing the expression of MYC, B-cell lymphoma XL (BCL-XL) and cyclin D1. It also contributes to the increased production of reactive oxygen species (ROS) by MDSCs. The activation of STAT6 and STAT1, as well as Toll-like receptor (TLR)-mediated activation of nuclear factor-κB (NF-κB), by these factors results in the activation of MDSCs, which leads to the upregulation of arginase 1 and inducible nitric oxide synthase (iNOS), and to the increased production of suppressive cytokines, such as transforming growth factor-β (TGFβ). In combination with STAT3, STAT1 and STAT6 also contribute to upregulation of ROS production by MDSCs (not shown). S100 calcium-binding proteinA8 (S100A8) and S100A9 directly bind to components of NADPH oxidase complex. This binding potentiates the activation of NADPH oxidase in MDSCs, which causes increased production of ROS, thereby leading to the observed suppressive effects. It is probable that MDSC activation through TLRs has an important role during pathogenic infections. G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte/ macrophage CSF; IFNγ, interferon-γ; IL, interleukin; JAK, Janus kinase; M-CSF, macrophage CSF; MyD88, myeloid differentiation primary-response gene 88; Phox, phagocyte oxidase; VEGF, vascular endothelial growth factor.
Figure 3 | Suppressive mechanisms mediated by different subsets of mDSCs. Myeloid-derived suppressor cells (MDSCs) consist of two main subsets: monocytic MDSCs, which have a CD11b+ LY6G– LY6Chi phenotype, and granulocytic MDSCs, which have a CD11b+ LY6G+ LY6Clow phenotype. In most tumour models, it is predominantly (70–80%) the granulocytic subset of MDSCs that expands. We suggest that the granulocytic subset of MDSCs has increased activity of signal transducer and activator of transcription 3 (STAT3) and NADPH, which results in high levels of reactive oxygen species (ROS) but low nitric oxide (NO) production. ROS and, in particular, peroxynitrite (the product of a chemical reaction between superoxide anion and NO) induces the post-translational modification of T-cell receptors and may cause antigen-specific T-cell unresponsiveness. The monocytic MDSC subset has upregulated expression of STAT1 and inducible nitric oxide synthase (iNOS), and increased levels of NO but low ROS production. NO, which is produced by the metabolism of l-arginine by iNOS, suppresses T-cell function through various different mechanisms that involve the inhibition of Janus kinase 3 and STAT5, the inhibition of MHC class II expression and the induction of T-cell apoptosis. Both subsets have increased levels of arginase 1, which causes T-cell suppression through depletion of l-arginine. Only monocytic MDSCs can differentiate into mature dendritic cells and macrophages in vitro.
Figure 4 | The mechanisms of mDSC-mediated immune suppression differ in peripheral lymphoid organs and at the site of a tumour. Myeloid-derived suppressor cells (MDSCs) migrate to tumour sites and peripheral lymphoid organs. a | In peripheral lymphoid organs, MDSCs produce high levels of reactive oxygen species (ROS), including peroxynitrite (ONOO– ), and upregulate signal transducer and activator of transcription 3 (STAT3) activity. This is associated with a moderate increase in arginase 1 activity and low levels of nitric oxide (NO) production. MDSCs can take up, process and present antigens to antigen-specific CD8+ T cells. During this close cell–cell contact, peroxynitrite produced by MDSCs causes nitration and nitrosylation of different amino acids on the T-cell receptor (TCR) and CD8 molecules on the surface of T cells, which causes the T cells to become unresponsive to antigen-specific stimulation. However, these cells retain the ability to respond to antigen-non-specific stimulation with CD3- and CD28-specific antibodies. b | By contrast, MDSCs that migrate to the site of the tumour upregulate STAT1 activity, produce high levels of inducible nitric oxide synthase (iNOS), NO and arginase 1; this is associated with low levels of ROS. The high levels of arginase 1 and NO that are released by MDSCs inhibit CD8+ T-cell function in a non-specific manner. MDSCs at the tumour site can also differentiate into tumour-associated macrophages (TAMs). In contrast to MDSCs, TAMs upregulate the expression of either arginase 1 or iNOS, depending on the nature of the tumour microenvironment (see rEF. 91), but not of both proteins. TAMs acquire the ability to produce several suppressive cytokines, such as interleukin-1β (IL-1β), IL-6, IL-10 and transforming growth factor-β (TGFβ). Together with MDSCs, TAMs contribute to antigen-non-specific T-cell suppression in the tumour microenvironment.
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