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Human endothelial cells generate Th17 and regulatory T cells under inflammatory conditions.

ABSTRACT: Organ transplantation represents a unique therapeutic option for irreparable organ dysfunction and rejection of transplants results from a breakdown in operational tolerance. Although endothelial cells (ECs) are the first target in graft rejection following kidney transplantation, their capacity to alloactivate and generate particular T lymphocyte subsets that could intervene in this process remains unknown. By using an experimental model of microvascular endothelium, we demonstrate that, under inflammatory conditions, human ECs induced proliferation of memory CD4(+)CD45RA(-) T cells and selectively amplified proinflammatory Th17 and suppressive CD45RA(-)HLA-DR(+)FoxP3(bright) regulatory CD4(+) T lymphocytes (Tregs). Although HLA-DR expression on resting microvascular ECs was sufficient to induce proliferation of memory CD4(+) T cells, Treg amplification was dependent on the interaction with CD54, highly expressed only under inflammatory conditions. Moreover, expansion of Th17 cells was dependent on IL-6 and STAT-3, and inhibition of either specifically impaired Th17, without altering Treg expansion. Collectively these data reveal that the HLA-DR(+) ECs regulate the local inflammatory allogeneic response, promoting either an IL-6/STAT-3-dependent Th17 response or a contact-CD54-dependent regulatory response according to the cytokine environment. Finally, these data open therapeutic perspectives in human organ transplantation based on targeting the IL-6/STAT-3 pathway and/or promoting CD54 dependent Treg proliferation.

SUBMITTER: Taflin C

PROVIDER: S-EPMC3041137 | biostudies-other | 2011 Feb

REPOSITORIES: biostudies-other

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Project description:PurposeMost tumours are characterized by an inflammatory microenvironment, and correlations between inflammation and cancer progression have been shown. Endothelial cells (ECs), as part of the tumour microenvironment, play a crucial role in inflammatory processes as well as in angiogenesis and could be critical targets of cancer therapy like irradiation. Therefore, in the present study we investigated the effect of ionizing radiation on endothelial cells under inflammatory conditions and their interactions with tumour cells.MethodsNonactivated and TNF-α treatment-activated human EC EA.hy926 were irradiated with doses between 0.1 Gy and 6 Gy with a linear accelerator. Using a multiplex assay, the accumulation of various chemokines (IL-8, MCP-1, E-selectin, and P-selectin) and soluble adhesion molecules (sICAM-1 and VCAM-1) as well as protein values of the vascular endothelial growth factor (VEGF) was measured in the supernatant at different time points. The adhesion capability of irradiated and nonirradiated A549 tumour cells to EA.hy926 cells was measured using flow cytometry, and the migration of tumour cells was investigated with a scratch motility assay.ResultsIn contrast to unirradiated cells, IR of ECs resulted in a modified release of chemokines IL-8 and MCP-1 as well as the adhesion molecules sICAM-1 and VCAM-1 in the EC, whereas concentrations of E-selectin and P-selectin as well as VEGF were not influenced. IR always affected the adhesion capability of tumour cells to ECs with the effect dependent on the IR-treated cell type. TNF-α treatment generally increased adhesion ability of the tumour cells. Tumour cell migration was clearly inhibited after IR. This inhibitory effect was eliminated for radiation doses from 0.5 to 2 Gy when, additionally, an inflammatory environment was predominant.ConclusionsOur results support past findings suggesting that ECs, as part of the inflammatory microenvironment of tumours, are important regulators of the actual tumour response to radiation therapy.

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Human endothelial cells generate Th17 and regulatory T cells under inflammatory conditions.

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