PD-1 signaling uncovers a pathogenic subset of T cells in inflammatory arthritis.

Autor: Straube J; Columbia Center for Translational Immunology, Columbia University Medical Center, 650 W 168 St. BB-1701F, New York, NY, 10032, USA.; Institute of Anatomy and Cell Biology, Faculty of Medicine, Martin Luther University Halle-Wittenberg, 06099, Halle (Saale), Germany., Bukhari S; Columbia Center for Translational Immunology, Columbia University Medical Center, 650 W 168 St. BB-1701F, New York, NY, 10032, USA., Lerrer S; Columbia Center for Translational Immunology, Columbia University Medical Center, 650 W 168 St. BB-1701F, New York, NY, 10032, USA., Winchester RJ; Columbia Center for Translational Immunology, Columbia University Medical Center, 650 W 168 St. BB-1701F, New York, NY, 10032, USA.; Division of Rheumatology, Department of Medicine, Columbia University Medical Center, New York, NY, 10032, USA., Gartshteyn Y; Division of Rheumatology, Department of Medicine, Columbia University Medical Center, New York, NY, 10032, USA., Henick BS; Herbert Irving Cancer Center, Columbia University Medical Center, New York, NY, 10032, USA., Dragovich MA; Columbia Center for Translational Immunology, Columbia University Medical Center, 650 W 168 St. BB-1701F, New York, NY, 10032, USA., Mor A; Columbia Center for Translational Immunology, Columbia University Medical Center, 650 W 168 St. BB-1701F, New York, NY, 10032, USA. am5121@cumc.columbia.edu.; Division of Rheumatology, Department of Medicine, Columbia University Medical Center, New York, NY, 10032, USA. am5121@cumc.columbia.edu.; Herbert Irving Cancer Center, Columbia University Medical Center, New York, NY, 10032, USA. am5121@cumc.columbia.edu.
Jazyk: angličtina
Zdroj: Arthritis research & therapy [Arthritis Res Ther] 2024 Jan 22; Vol. 26 (1), pp. 32. Date of Electronic Publication: 2024 Jan 22.
DOI: 10.1186/s13075-023-03259-5
Abstrakt: Background: PD-1 is an immune checkpoint on T cells, and interventions to block this receptor result in T cell activation and enhanced immune response to tumors and pathogens. Reciprocally, despite a decade of research, approaches to treat autoimmunity with PD-1 agonists have only had limited successful. To resolve this, new methods must be developed to augment PD-1 function beyond engaging the receptor.
Methods: We conducted a flow cytometry analysis of T cells isolated from the peripheral blood and synovial fluid of patients with rheumatoid arthritis. In addition, we performed a genome-wide CRISPR/Cas9 screen to identify genes associated with PD-1 signaling. We further analyzed genes involved in PD-1 signaling using publicly available bulk and single-cell RNA sequencing datasets.
Results: Our screen confirmed known regulators in proximal PD-1 signaling and, importantly, identified an additional 1112 unique genes related to PD-1 ability to inhibit T cell functions. These genes were strongly associated with the response of cancer patients to PD-1 blockades and with high tumor immune dysfunction and exclusion scores, confirming their role downstream of PD-1. Functional annotation revealed that the most significant genes uncovered were those associated with known immune regulation processes. Remarkably, these genes were considerably downregulated in T cells isolated from patients with inflammatory arthritis, supporting their overall inhibitory functions. A study of rheumatoid arthritis single-cell RNA sequencing data demonstrated that five genes, KLRG1, CRTAM, SLAMF7, PTPN2, and KLRD1, were downregulated in activated and effector T cells isolated from synovial fluids. Backgating these genes to canonical cytotoxic T cell signatures revealed PD-1 + HLA-DR HIGH KLRG1 LOW T cells as a novel inflammatory subset of T cells.
Conclusions: We concluded that PD-1 + HLA-DR HIGH KLRG1 LOW T cells are a potential target for future PD-1 agonists to treat inflammatory diseases. Our study uncovers new genes associated with PD-1 downstream functions and, therefore, provides a comprehensive resource for additional studies that are much needed to characterize the role of PD-1 in the synovial subset of T cells.
(© 2024. The Author(s).)
Databáze: MEDLINE
Externí odkaz: