Dataset Information

A Comparative Study of the T Cell Stimulatory and Polarizing Capacity of Human Primary Blood Dendritic Cell Subsets.

ABSTRACT: Dendritic cells (DCs) are central players of immune responses; they become activated upon infection or inflammation and migrate to lymph nodes, where they can initiate an antigen-specific immune response by activating naive T cells. Two major types of naturally occurring DCs circulate in peripheral blood, namely, myeloid and plasmacytoid DCs (pDCs). Myeloid DCs (mDCs) can be subdivided based on the expression of either CD1c or CD141. These human DC subsets differ in surface marker expression, Toll-like receptor (TLR) repertoire, and transcriptional profile, suggesting functional differences between them. Here, we directly compared the capacity of human blood mDCs and pDCs to activate and polarize CD4(+) T cells. CD141(+) mDCs show an overall more mature phenotype over CD1c(+) mDC and pDCs; they produce less IL-10 and more IL-12 than CD1c(+) mDCs. Despite these differences, all subsets can induce the production of IFN-? in naive CD4(+) T cells. CD1c(+) and CD141(+) mDCs especially induce a strong T helper 1 profile. Importantly, naive CD4(+) T cells are not polarized towards regulatory T cells by any subset. These findings further establish all three human blood DCs-despite their differences-as promising candidates for immunostimulatory effectors in cancer immunotherapy.

SUBMITTER: Sittig SP

PROVIDER: S-EPMC4761397 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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A Comparative Study of the T Cell Stimulatory and Polarizing Capacity of Human Primary Blood Dendritic Cell Subsets.

Sittig Simone P SP Bakdash Ghaith G Weiden Jorieke J Sköld Annette E AE Tel Jurjen J Figdor Carl G CG de Vries I Jolanda M IJ Schreibelt Gerty G

Mediators of inflammation 20160207

Dendritic cells (DCs) are central players of immune responses; they become activated upon infection or inflammation and migrate to lymph nodes, where they can initiate an antigen-specific immune response by activating naive T cells. Two major types of naturally occurring DCs circulate in peripheral blood, namely, myeloid and plasmacytoid DCs (pDCs). Myeloid DCs (mDCs) can be subdivided based on the expression of either CD1c or CD141. These human DC subsets differ in surface marker expression, To ...[more]

PMID: 27057096

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Project description:Dendritic cells (DC) are critically involved in decisions related to the acceptance or rejection of the foreign fetal antigens by the maternal immune system. However, particularly for human peripheral blood DCs (PBDC), available literature is rather inconsistent and the factors regulating these cells are ill-defined. Here, we investigated the phenotype and functionality of different human PBDC subsets during normal and pathologic pregnancies and studied an involvement of human chorionic gonadotropin (hCG) in PBDC regulation. Peripheral blood samples were obtained from normal pregnant women in all three trimesters, from first trimester miscarriage patients and from healthy non-pregnant women. Samples were analyzed for plasma hCG levels, for regulatory T (Treg) cell numbers, for frequencies of total and mature plasmacytoid (PDC) and myeloid (MDC1 and MDC2) PBDC subsets and for their cytokine secretion. In vitro assays, culturing PDC, MDC1 or MDC2 in the presence of two trophoblast cell lines, placenta explant supernatants or two hCG preparations were performed. The Treg-inducing capability of hCG- or non-hCG-treated stimulated MDC1 was assessed. Total and mature MDC1 and MDC2 frequencies increased during the first and second trimester of normal pregnancy, respectively. Miscarriage was associated with a reduced MDC1 and an increased MDC2 activation profile. PDC were not altered neither during normal pregnancy progression nor during miscarriage. In vitro, the culture of isolated PBDC subsets in the presence of placenta-derived factors impaired the maturation of MDC1 and differentially affected PDC maturation. An inhibitory effect on MDC1 and PDC maturation was also proven for the urine-derived hCG preparation. Finally, we observed a Treg cell elevation during early normal pregnancy that was not present in miscarriages. Stimulated MDC1 induced Treg cells in vitro, however, hCG was not involved in this process. Our findings suggest that during normal pregnancy PBDC subsets are differentially regulated dependent on gestational age. Miscarriage seems to be associated with dysregulations in the myeloid PBDC subsets and with disturbances in Treg cell frequencies. Moreover, our results propose an interdependency between MDC1 and Treg cells during early pregnancy. hCG, although shown to impair MDC1 maturation, does not seem to be a key regulator of PBDC alterations during pregnancy.

Project description:IntroductionThe broccoli isothiocyanate sulforaphane was shown to inhibit inflammation and tumor progression, also in pancreatic cancer, while its effect on tumor immunity is poorly understood. We investigated the immunoregulatory effect of sulforaphane on human dendritic cells alone and in presence of pancreatic tumor antigens, as well as underlying molecular mechanisms.MethodsSulforaphane-treated human dendritic cells were matured in vitro with a cytokine cocktail, and the expression of regulatory molecules was examined by flow cytometry. The subsequent T-cell response was analyzed by T-cell proliferation assay and CD25 expression. To confirm the findings, dendritic cells pulsed with pancreatic cancer-derived tumor antigens were used. To identify the involved pathway- and microRNA-signaling in sulforaphane-treated dendritic cells, inhibitors of various signaling pathways, western blot analysis, microRNA array, and bioinformatic analysis were applied.ResultsSulforaphane modulated the expression of the costimulatory CD80, CD83 and the suppressive B7-H1 molecules on dendritic cells and thereby promoted activation of T cells. The effect was verified in presence of pancreatic tumor antigens. Phosphorylation of STAT3 in dendritic cells was diminished by sulforaphane, and the inhibition of JAK/STAT3 led to downregulation of B7-H1 expression. Among the identified top 100 significant microRNA candidates, the inhibition of miR-155-5p, important for the expression of costimulatory molecules, and the induction of miR-194-5p, targeting the B7-H1 gene, were induced by sulforaphane.ConclusionOur findings demonstrate that sulforaphane promotes T-cell activation by dendritic cells through the modulation of regulatory molecules, JAK/STAT3- and microRNA-signaling in healthy conditions and in context of pancreatic cancer-derived antigens. They explore the immunoregulatory properties of sulforaphane and justify further research on nutritional strategies in the co-treatment of cancer.

Dataset Information

A Comparative Study of the T Cell Stimulatory and Polarizing Capacity of Human Primary Blood Dendritic Cell Subsets.

Publications

A Comparative Study of the T Cell Stimulatory and Polarizing Capacity of Human Primary Blood Dendritic Cell Subsets.

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