Fanelli and Romano et al. showed that human blood CD4+CD25- T cells stimulated by crosslinked anti-CD3 or anti-CD3/anti-CD28 expressed PD-L1 and PD-1. Crosslinked anti-CD3/anti-PD-L1 stimulated CD4+CD25- T cell proliferation and conversion to IFNγ/IL-10-producing inducible Tregs (iTregs) with increased CD25, FOXP3, PD-1, CTLA-4, CD28, ICOS, and OX40 expression. Conversion occurred in memory (but not naive) T cells, even if cells were gene edited to be PD-1-deficient. Anti-CD3/anti-PD-L1 stimulation reduced AKT/mTOR and TCR/MAPK signaling (but not in cells from patients with RA) to mediate suppression of effector T cells.
Contributed by Paula Hochman
ABSTRACT: Programmed death cell receptor 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.
Author Info: (1) MRC Centre for Transplantation, School of Immunology and Microbial Sciences, King's College London, Guy's Hospital, London, United Kingdom. (2) MRC Centre for Transplantation,
Author Info: (1) MRC Centre for Transplantation, School of Immunology and Microbial Sciences, King's College London, Guy's Hospital, London, United Kingdom. (2) MRC Centre for Transplantation, School of Immunology and Microbial Sciences, King's College London, Guy's Hospital, London, United Kingdom. (3) MRC Centre for Transplantation, School of Immunology and Microbial Sciences, King's College London, Guy's Hospital, London, United Kingdom. (4) Cancer Immunology Unit, University College London (UCL) Cancer Institute, London, United Kingdom. (5) Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University of London and Barts' Health NHS Trust, London, United Kingdom. (6) MRC Centre for Transplantation, School of Immunology and Microbial Sciences, King's College London, Guy's Hospital, London, United Kingdom. (7) Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University of London and Barts' Health NHS Trust, London, United Kingdom. (8) Cancer Immunology Unit, University College London (UCL) Cancer Institute, London, United Kingdom. (9) MRC Centre for Transplantation, School of Immunology and Microbial Sciences, King's College London, Guy's Hospital, London, United Kingdom. (10) Department of Microbiology and Immunology, Norris Cotton Cancer Center Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, United States of America. (11) Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University of London and Barts' Health NHS Trust, London, United Kingdom. (12) MRC Centre for Transplantation, School of Immunology and Microbial Sciences, King's College London, Guy's Hospital, London, United Kingdom. King's Health Partners, London, United Kingdom. (13) MRC Centre for Transplantation, School of Immunology and Microbial Sciences, King's College London, Guy's Hospital, London, United Kingdom. (14) MRC Centre for Transplantation, School of Immunology and Microbial Sciences, King's College London, Guy's Hospital, London, United Kingdom.
