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Human trophoblast cells induced MDSCs from peripheral blood CD14(+) myelomonocytic cells via elevated levels of CCL2.

ABSTRACT: Successful human pregnancy requires the maternal immune system to recognize and tolerate the semi-allogeneic fetus. Myeloid-derived suppressor cells (MDSCs), which are capable of inhibiting T-cell responses, are highly increased in the early stages of pregnancy. Although recent reports indicate a role for MDSCs in fetal-maternal tolerance, little is known about the expansion of MDSCs during pregnancy. In the present study, we demonstrated that the trophoblast cell line HTR8/SVneo could instruct peripheral CD14(+) myelomonocytic cells toward a novel subpopulation of MDSCs, denoted as CD14(+)HLA-DR(-/low) cells, with suppressive activity and increased expression of IDO1, ARG-1, and COX2. After interaction with HTR8/SVneo cells, CD14(+) myelomonocytic cells secrete high levels of CCL2, promoting the expression of signal transducer and activator of transcription 3. We utilized a neutralizing monoclonal antibody to reveal the prominent role of CCL2 in the induction of CD14(+)HLA-DR(-/low) MDSCs. In combination, the results of the present study support a novel role for the cross-talk between the trophoblast cell line HTR8/SVneo and maternal CD14(+) myelomonocytic cells in initiating MDSCs induction, prompting a tolerogenic immune response to ensure a successful pregnancy.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC5037277 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Human trophoblast cells induced MDSCs from peripheral blood CD14(+) myelomonocytic cells via elevated levels of CCL2.

Zhang Yun Y Qu Daiwei D Sun Jintang J Zhao Lei L Wang Qingjie Q Shao Qianqian Q Kong Beihua B Zhang Yun Y Qu Xun X

Cellular & molecular immunology 20150601 5

Successful human pregnancy requires the maternal immune system to recognize and tolerate the semi-allogeneic fetus. Myeloid-derived suppressor cells (MDSCs), which are capable of inhibiting T-cell responses, are highly increased in the early stages of pregnancy. Although recent reports indicate a role for MDSCs in fetal-maternal tolerance, little is known about the expansion of MDSCs during pregnancy. In the present study, we demonstrated that the trophoblast cell line HTR8/SVneo could instruct ...[more]

PMID: 26027727

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Project description:BackgroundSystemic sclerosis (SSc) is an autoimmune disease characterized by overproduction of extracellular matrix (ECM) and multiorgan fibrosis. Animal studies pointed to bone marrow-derived cells as a potential source of pathological ECM-producing cells in immunofibrotic disorders. So far, involvement of monocytes and macrophages in the fibrogenesis of SSc remains poorly understood.Methods and resultsImmunohistochemistry analysis showed accumulation of CD14+ monocytes in the collagen-rich areas, as well as increased amount of alpha smooth muscle actin (αSMA)-positive fibroblasts, CD68+ and mannose-R+ macrophages in the heart and lungs of SSc patients. The full genome transcriptomics analyses of CD14+ blood monocytes revealed dysregulation in cytoskeleton rearrangement, ECM remodeling, including elevated FN1 (gene encoding fibronectin) expression and TGF-β signalling pathway in SSc patients. In addition, single cell RNA sequencing analysis of tissue-resident CD14+ pulmonary macrophages demonstrated activated profibrotic signature with the elevated FN1 expression in SSc patients with interstitial lung disease. Peripheral blood CD14+ monocytes obtained from either healthy subjects or SSc patients exposed to profibrotic treatment with profibrotic cytokines TGF-β, IL-4, IL-10, and IL-13 increased production of type I collagen, fibronectin, and αSMA. In addition, CD14+ monocytes co-cultured with dermal fibroblasts obtained from SSc patients or healthy individuals acquired a spindle shape and further enhanced production of profibrotic markers. Pharmacological blockade of the TGF-β signalling pathway with SD208 (TGF-β receptor type I inhibitor), SIS3 (Smad3 inhibitor) or (5Z)-7-oxozeaenol (TGF-β-activated kinase 1 inhibitor) ameliorated fibronectin levels and type I collagen secretion.ConclusionsOur findings identified activated profibrotic signature with elevated production of profibrotic fibronectin in CD14+ monocytes and CD14+ pulmonary macrophages in SSc and highlighted the capability of CD14+ monocytes to acquire a profibrotic phenotype. Taking together, tissue-infiltrating CD14+ monocytes/macrophages can be considered as ECM producers in SSc pathogenesis.

Project description:Human granulocytic myeloid-derived suppressor cells (G-MDSCs) have been described as low-density immunosuppressive CD66b+CD33dimHLA-DR-granulocytes that co-purify with mononuclear cells after density gradient centrifugation of blood from cancer patients. The role of G-MDSCs in Hodgkin (HL) and non-Hodgkin lymphoma (NHL) remains unclear.The percentage and immunophenotype of CD66b+CD33dimHLA-DR-cells were analyzed in PBMCs from HL and B-cell NHL patients (n = 124) and healthy donors (n = 48). The immunosuppressive functions of these cells were tested in vitro. Correlations between CD66b+CD33dimHLA-DR-cells and patient clinicopathological features and outcome, were evaluated.CD66b+CD33dimHLA-DR-cells were increased in PBMCs from HL and B-cell NHL patients as compared to healthy donors: 2.18 (0.02-70.92) vs 0.42 (0.04-2.97), p < 0.0001. Their percentage remained significantly higher even considering HL (n = 31), indolent (n = 31) and aggressive (n = 62) B-cell NHL patients separately: 1.54 (0.28-26.34), 2.15 (0.02-20.08), and 2.96 (0.25-70.92), respectively, p < 0.0001. CD66b+CD33dimHLA-DR-cells in patient PBMCs were mostly composed of mature CD11b+CD16+ low-density neutrophils in an activated status, as revealed by their higher CD11b and CD66b expression as compared to conventionally isolated (normal-density) autologous or healthy donor neutrophils. The in vitro depletion of CD66b+ cells from patient PBMCs restored the proliferation of autologous T cells. Higher frequencies of CD66b+CD33dimHLA-DR- G-MDSCs correlated significantly with unfavorable prognostic index scores and a shorter freedom from disease progression.PBMCs from HL and B-cell NHL patients contain a population of CD66b+CD33dimHLA-DR- G-MDSCs, mostly composed of activated low-density neutrophils with immunosuppressive properties. These findings disclose a previously unknown G-MDSC-mediated mechanism of immune-escape in lymphomas, therefore anticipating possible targets for therapeutic interventions.

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Human trophoblast cells induced MDSCs from peripheral blood CD14(+) myelomonocytic cells via elevated levels of CCL2.

Publications

Human trophoblast cells induced MDSCs from peripheral blood CD14(+) myelomonocytic cells via elevated levels of CCL2.

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