PD-L1 signaling on human memory CD4+ T cells induces a regulatory phenotype

Fanelli, Giorgia and Romano, Marco and Nova-Lamperti, Estefania and Werner Sunderland, Mariana and Nerviani, Alessandra and Scottà, Cristiano and Bombardieri, Michele and Quezada, Sergio A. and Sacks, Steven H. and Noelle, Randolph J. and Pitzalis, Costantino and Lechler, Robert I. and Lombardi, Giovanna and Becker, Pablo D. and Oliver, Paula M. (2021) PD-L1 signaling on human memory CD4+ T cells induces a regulatory phenotype. PLOS Biology, 19 (4). e3001199. ISSN 1545-7885

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Abstract

Programmed cell death protein 1 (PD-1) is expressed on T cells upon T cell receptor (TCR) stimulation. PD-1 ligand 1 (PD-L1) is expressed in most tumor environments, and its binding to PD-1 on T cells drives them to apoptosis or into a regulatory phenotype. The fact that PD-L1 itself is also expressed on T cells upon activation has been largely neglected. Here, we demonstrate that PD-L1 ligation on human CD25-depleted CD4+ T cells, combined with CD3/TCR stimulation, induces their conversion into highly suppressive T cells. Furthermore, this effect was most prominent in memory (CD45RA−CD45RO+) T cells. PD-L1 engagement on T cells resulted in reduced ERK phosphorylation and decreased AKT/mTOR/S6 signaling. Importantly, T cells from rheumatoid arthritis patients exhibited high basal levels of phosphorylated ERK and following PD-L1 cross-linking both ERK signaling and the AKT/mTOR/S6 pathway failed to be down modulated, making them refractory to the acquisition of a regulatory phenotype. Altogether, our results suggest that PD-L1 signaling on memory T cells could play an important role in resolving inflammatory responses; maintaining a tolerogenic environment and its failure could contribute to ongoing autoimmunity.

Item Type: Article
Subjects: Journal Eprints > Biological Science
Depositing User: Managing Editor
Date Deposited: 18 Mar 2023 07:33
Last Modified: 03 Aug 2024 13:04
URI: http://repository.journal4submission.com/id/eprint/802

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