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.
Highlights
Therapies for autoimmune diseases and chronic inflammation are mainly directed toward reestablishing a balance in the immune system
We demonstrated that cross-linking of PD-1 ligand 1 (PD-L1) on CD4+CD25− T cells, in combination with CD3/T cell receptor (TCR), induced their conversion into highly suppressive inducible regulatory T cell (Treg) (iTreg) from the memory pool by modulating the mitogen-activated protein kinase (MAPK) pathway, increasing STAT3 and STAT5 phosphorylation and decreasing ERK phosphorylation downstream to the TCR signaling pathway and antagonizing the AKT/mTOR pathway
Our study demonstrates that PD-L1, like the canonical costimulatory molecule CD28, supports TCR signaling for an optimal induction of T cell activation and proliferation
Summary
Therapies for autoimmune diseases and chronic inflammation are mainly directed toward reestablishing a balance in the immune system. London and/or the NIHR Clinical Research Facility. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. We acknowledge Research Councils United Kingdom (RCUK) for the support. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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