Taylor, A orcid.org/0000-0003-2295-2611 and Rudd, CE (2017) Glycogen synthase kinase 3 (GSK-3) inactivation compensates for the lack of CD28 in the priming of CD8+ cytotoxic T-cells: implications for anti-PD-1 immunotherapy. Frontiers in Immunology, 8 (Dec). ARTN 1653. ISSN 1664-3224
Abstract
The rescue of exhausted CD8+ cytolytic T-cells (CTLs) by anti-PD-1 blockade has been found to require CD28 expression. At the same time, we have shown that the inactivation of the serine/threonine kinase GSK‐3α/β with small interfering RNAs (siRNAs) and small molecule inhibitors (SMIs) specifically down-regulate PD-1 expression for enhanced CD8+ CTL function and clearance of tumours and viral infections. Despite this, it has been unclear whether the GSK‐3α/β pathway accounts for CD28 co‐stimulation of CD8+ CTL function. In this paper, we show that inactivation of GSK‐3α/β through siRNA or by SMIs during priming can substitute CD28 stimulation in the potentiation of cytotoxic CD8+ CTL function. This increased response was observed in the blockade of CD28 co-receptor by CTLA-4-IgG in OT-1 T-cells responding to OVA peptide as presented by the lymphoma cell line EL4. The effect was seen using several GSK-3 SMIs, and was accompanied by an increase in Lamp-1 and GZMB expression. Conversely, CD28 crosslinking obviated the need for GSK‐3α/β inhibition in its enhancement of CTL function. Our findings support a model where GSK‐3 is the central co-signal for CD28 priming of CD8+ CTLs in anti-PD-1 immunotherapy.
Metadata
Item Type: | Article |
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Copyright, Publisher and Additional Information: | © 2017 Taylor and Rudd. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
Keywords: | T-cells, GSK-3 (Glycogen synthase kinase 3), cytotoxic T-cells, CD8+ T-cell response, CD28 co-stimulation, CD28 blockade |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cancer and Pathology (LICAP) |
Funding Information: | Funder Grant number Cancer Research UK C11071/A20105 |
Depositing User: | Symplectic Publications |
Date Deposited: | 21 Nov 2017 16:06 |
Last Modified: | 12 Jan 2018 15:30 |
Status: | Published |
Publisher: | Frontiers Media |
Identification Number: | 10.3389/fimmu.2017.01653 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:124059 |