Open AccessPD-L1 signaling on human memory CD4+ T cells induces a regulatory phenotype
Author(s) -
Giorgia Fanelli,
Marco Romano,
Estefanía Nova-Lamperti,
Mariana Werner Sunderland,
Alessandra Nerviani,
Cristiano Scottà,
Michèle Bombardieri,
Sergio A. Quezada,
Steven Sacks,
Randolph J. Noelle,
Costantino Pitzalis,
Robert I. Lechler,
Giovanna Lombardi,
Pablo D. Becker
Publication year - 2021
Publication title -
plos biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.127
H-Index - 271
eISSN - 1545-7885
pISSN - 1544-9173
DOI - 10.1371/journal.pbio.3001199
Subject(s) - biology , il 2 receptor , microbiology and biotechnology , t cell receptor , phosphorylation , pi3k/akt/mtor pathway , protein kinase b , t cell , mapk/erk pathway , zap70 , signal transduction , cd8 , cancer research , immunology , immune system
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.