PD-L1 partially protects renal tubular epithelial cells from the attack of CD8+cytotoxic T cells
| Autor: | Ying Waeckerle-Men, Rudolf P. Wüthrich, Astrid Starke |
|---|---|
| Přispěvatelé: | University of Zurich, Waeckerle-Men, Y |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Cytotoxicity
Immunologic 2747 Transplantation medicine.medical_treatment T cell Down-Regulation 610 Medicine & health Mice Transgenic Major histocompatibility complex B7-H1 Antigen 10052 Institute of Physiology Cell Line Kidney Tubules Proximal Interleukin 21 Interferon-gamma Mice medicine Cytotoxic T cell Animals 10035 Clinic for Nephrology Transplantation Mice Inbred C3H 2727 Nephrology Membrane Glycoproteins biology CD28 Epithelial Cells hemic and immune systems Interferon-beta Molecular biology Up-Regulation Mice Inbred C57BL CTL Cytokine medicine.anatomical_structure Nephrology 10076 Center for Integrative Human Physiology Immunology biology.protein B7-1 Antigen 570 Life sciences Peptides CD8 T-Lymphocytes Cytotoxic |
| Popis: | 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-alpha, IFN-beta or IFN-gamma). 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-2K(b)-restricted, OVA(257-264) peptide-specific CD8+ T cells isolated from OT-1 T cell receptor transgenic mice were co-incubated with IFN-stimulated, OVA(257-264) peptide-pulsed congeneic TEC. The activation of OT-1 CD8+ CTL was estimated either by IFN-gamma 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-beta or IFN-gamma, but not with IFN-alpha. OVA(257-264) peptide pulsed-TEC were able to activate OT-1 CD8+ T cells, indicated by the high amount of IFN-gamma 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- beta- or IFN-gamma-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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|