Glycogen Synthase Kinase 3 Inactivation Compensates for the Lack of CD28 in the Priming of CD8+ Cytotoxic T-Cells: Implications for anti-PD-1 Immunotherapy.

Alison Taylor,Christopher E Rudd

doi:10.3389/fimmu.2017.01653

Abstract

The rescue of exhausted CD8+ cytolytic T-cells (CTLs) by anti-Programmed Cell Death-1 (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 glycogen synthase kinase (GSK)-3α/β with small-interfering RNAs (siRNAs) and small molecule inhibitors (SMIs) specifically down-regulates PD-1 expression for enhanced CD8+ CTL function and clearance of tumors and viral infections. Despite this, it has been unclear whether the GSK-3α/β pathway accounts for CD28 costimulation of CD8+ CTL function. In this article, we show that inactivation of GSK-3α/β through siRNA or by SMIs during priming can substitute CD28 co-stimulation in the potentiation of cytotoxic CD8+ CTL function against the EL-4 lymphoma cells expressing OVA peptide. The effect was seen using several structurally distinct 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 cosignal for CD28 priming of CD8+ CTLs in anti-PD-1 immunotherapy.

Highlights

Naive T-cells are cells that have not encountered cognate antigen are essential for responses to novel pathogens
We recently showed that glycogen synthase kinase (GSK)-3 is a central regulator of Programmed cell death 1 (PD-1) expression and that the inactivation of glycogen synthase kinase-3 (GSK-3) using small molecule inhibitors (SMIs) downregulates PD-1 expression resulting in enhanced clearance of viral infections and cancer [44, 45]
We propose that GSK-3 is the key mediator that is responsible for CD28 priming of CD8+ CTLs in T-cell immunity and in response to anti-PD-1 Immune checkpoint blockade (ICB) immunotherapy

Summary

Introduction

Naive T-cells are cells that have not encountered cognate antigen are essential for responses to novel pathogens. In this instance, activation requires a combination of stimulatory signals [1]. The first signal is provided by the T-cell receptor (TCR) upon lymphocyte interaction with major histocompatibility class (MHC) antigens on the antigen-presenting cells (APCs) within the immune synapse [2]. The second signal for T-cell activation is provided by CD28 and other costimulatory coreceptors on T-cells [3,4,5,6]. TCR signaling alone can result in the lymphocyte undergoing cell death, or becoming anergic and unable to respond to antigen [9].

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