NDT Advance Access originally published online on March 5, 2007
Nephrology Dialysis Transplantation 2007 22(6):1527-1536; doi:10.1093/ndt/gfl818
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PD-L1 partially protects renal tubular epithelial cells from the attack of CD8+cytotoxic T cells
1Institute of Physiology and Zurich Center for Integrative Human Physiology, University of Zürich-Irchel and 2Clinic for Nephrology, University Hospital Zürich, Switzerland
Correspondence and offprint requests to: Dr Y. Waeckerle-Men, Institute of Physiology, University of Zurich-Irchel, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. Email: ying.waeckerle-men{at}access.unizh.ch
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Abstract |
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Background. Activated infiltrating T cells play a crucial role in nephritic inflammation via the direct interaction with proximal tubular epithelial cells (TEC). Under inflammatory conditions, major histocompatibility complex class I and II molecules are upregulated on the surface of renal TEC, enabling them to function as ‘non-professional’ antigen-presenting cells (APC) to activate T cells, and, in turn to be targeted by cytotoxic T lymphocytes (CTL) to cause tissue damage. It is known that co-stimulatory (e.g. B7/CD28) and co-inhibitory (e.g. PD-L1/PD-1) signals regulate and determine the magnitude of T cell responses. In this study, we examined the expression of co-stimulatory molecule PD-L1 by renal TEC and the functional role of renal PD-L1/PD-1 pathway in regulating CD8+ T cell responses induced by antigen-presenting renal TEC.
Methods. Renal TEC were treated with type I and type II interferons (IFN-
, IFN-ß or IFN-
). PD-L1 expression was then determined with flow cytometry and RT-PCR. To investigate the functional role of renal epithelial PD-L1 on CD8+ CTL responses, H-2Kb-restricted, OVA257–264 peptide-specific CD8+ T cells isolated from OT-1 T cell receptor transgenic mice were co-incubated with IFN-stimulated, OVA257–264 peptide-pulsed congeneic TEC. The activation of OT-1 CD8+ CTL was estimated either by IFN- production in the supernatants of co-cultures or by CTL activity.
Results. TECs do not constitutively express PD-L1 on their surface. However, a strong and dose-dependent upregulation of PD-L1 was observed on TEC after stimulation with IFN-ß or IFN-, but not with IFN-. OVA257–264 peptide pulsed-TEC were able to activate OT-1 CD8+ T cells, indicated by the high amount of IFN- production and cytolysis of TEC. Blockade of epithelial PD-L1 with specific mAb significantly increased OT-1 CD8+ T cell activity, indicating that the PD-L1 pathway has a negative effect on CD8+ T cell responses. Moreover, IFN- ß- or IFN--stimulated TEC with high surface PD-L1 expression were more resistant to the cytolysis by OT-1 CTL.
Conclusion. Together our data reveal that the renal PD-L1/PD-1 pathway has a negative effect on CD8+ CTL activation. PD-L1 might, therefore, act as a protective molecule on TEC, downregulating the cytotoxic renal parenchymal immune response.
Keywords: CD8+ T cells; interferon; PD-L1; renal tubular epithelial cells
Received for publication: 9.11.06
Accepted in revised form: 18.12.06
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