Programmed Death Ligand 1 Plays a Neuroprotective Role in Experimental Autoimmune Neuritis by Controlling Peripheral Nervous System Inflammation of Rats

Abstract

Programmed death 1 (PD-1; CD279), a member of the CD28 family, is an inhibitory receptor on T cells and is responsible for T cell dysfunction in infectious diseases and cancers. The ligand for PD-1, programmed death ligand 1 (PD-L1; also known as B7-H1, CD274), is a member of the B7 family. The engagement of PD-1 with programmed death ligand can downregulate autoreactive T cells that participate in multiple autoimmune diseases. Experimental autoimmune neuritis (EAN) is an animal model of Guillain-Barré syndrome, and the pathogenesis of EAN is mediated principally through T cells and macrophages. In this study, we investigated the effects of PD-L1 in EAN rats. For preventative and therapeutic management, we administered PD-L1, which successfully decreased the severity of EAN; it alleviated the neurologic course of EAN, as well as inhibited the infiltration of inflammatory cells and demyelination of sciatic nerves. Our data revealed that PD-L1 treatment inhibited lymphocyte proliferation and altered T cell differentiation by inducing decreases in IFN-γCD4 Th1 cells and IL-17CD4 Th17 cells and increases in IL-4CD4 Th2 cells and Foxp3CD4 regulatory T cells. The expression levels of p-STAT3 and Foxp3 were significantly different in PD-L1-treated groups compared with the control group. Additionally, PD-L1 regulated the expression of Foxp3 and p-STAT3 in EAN, probably by inhibiting PI3K/AKT/mTOR signaling expression. In summary, PD-L1 is a potentially useful agent for the treatment of EAN because of its anti-inflammatory and neuroprotective effects.

Immune checkpoint inhibitors in cancer therapy: a focus on T‐regulatory cells

“…It has been reported that in patients with breast cancer and CRC, Tregs co‐express high levels of PD‐1 and CTLA‐4 within the TME to create an immune‐subversive environment for the survival of tumor cells . PD‐L1 can alter T‐cell differentiation pathway by reducing CD4 + IFNγ + Th1 and CD4 + IL17 + Th17 and increasing Treg activation probably by inhibiting the PI3K/AKT/mTOR signaling pathway . Additionally, it has been reported that upregulation of PD‐L1 in tumor cells and FOXP3 in intratumoral Tregs synergistically upregulates their expression in the TME of patients with breast cancer, which favors tumor immune evasion …”

“…17,50 PD-L1 can alter T-cell differentiation pathway by reducing CD4 + IFNc + Th1 and CD4 + IL17 + Th17 and increasing Treg activation probably by inhibiting the PI3K/AKT/ mTOR signaling pathway. 78 Additionally, it has been reported that upregulation of PD-L1 in tumor cells and FOXP3 in intratumoral Tregs synergistically upregulates their expression in the TME of patients with breast cancer, which favors tumor immune evasion. 79 EFFECT OF ANTI-PD-1 AND ANTI-PD-L1 ANTIBODIES ON TREGS PD-1/PD-L1 axis supports tumor immune evasion in many cancers, and blockade of this interaction using monoclonal antibodies against PD-1 or PD-L1 can lead to restoration of effector T-cell functions.…”

PD-L1 (Programmed Death Ligand 1) Protects Against Experimental Intracerebral Hemorrhage–Induced Brain Injury

“…In addition, our team and others reported that the engagement of PD-L1 with its receptor on T cells led to the development of functional Treg cells and the downregulation of T-cell responses. 29,30 PD-L1 administration significantly alleviated symptoms and suppressed disease progression in murine models of autoimmune disorders and graft-versus-host disease by promoting the development of Treg cells and inhibiting the differentiation of Th17 cells. [13][14][15]30,31 Consistent with those reports, we showed that the underlying mechanism for improving the aftermath of ICH involves a change in the balance of Treg/Th17 cells.…”

MicroRNA-15b Suppresses Th17 Differentiation and Is Associated with Pathogenesis of Multiple Sclerosis by Targeting O-GlcNAc Transferase

“…The supernatants were harvested for assay. Cytokines in supernatants, including IL-1b, IL-6, IL-10, IL-12, TNF-a, and TGF-b, were analyzed by using a multi-analyte ELISArray kit (Qiagen) according to the instructions of manufacturer as previously described (38).…”