PD-1 signaling uncovers a pathogenic subset of T cells in inflammatory arthritis
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. Paired to that, and despite a decade of research, approaches to treat autoimmunity with PD-1 agonists still need to be more 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, found an additional 1,112 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 more 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. Back-gating these genes to canonical cytotoxic T cell signatures revealed PD-1 + HLA-DR HIGH KLRG LOW T cells as a novel inflammatory subset of T cells.
Conclusion: We concluded that PD-1 + HLA-DR HIGH KLRG 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.
Errataetall: |
UpdateIn: Arthritis Res Ther. 2024 Jan 22;26(1):32. - PMID 38254179 |
---|---|
Medienart: |
E-Artikel |
Erscheinungsjahr: |
2023 |
---|---|
Erschienen: |
2023 |
Enthalten in: |
Zur Gesamtaufnahme - year:2023 |
---|---|
Enthalten in: |
bioRxiv : the preprint server for biology - (2023) vom: 17. Nov. |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Straube, Johanna [VerfasserIn] |
---|
Links: |
---|
Themen: |
---|
Anmerkungen: |
Date Revised 26.02.2024 published: Electronic UpdateIn: Arthritis Res Ther. 2024 Jan 22;26(1):32. - PMID 38254179 Citation Status PubMed-not-MEDLINE |
---|
doi: |
10.1101/2023.11.16.566893 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
NLM365055204 |
---|
LEADER | 01000caa a22002652 4500 | ||
---|---|---|---|
001 | NLM365055204 | ||
003 | DE-627 | ||
005 | 20240229154641.0 | ||
007 | cr uuu---uuuuu | ||
008 | 231226s2023 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1101/2023.11.16.566893 |2 doi | |
028 | 5 | 2 | |a pubmed24n1306.xml |
035 | |a (DE-627)NLM365055204 | ||
035 | |a (NLM)38014321 | ||
035 | |a (PII)2023.11.16.566893 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a Straube, Johanna |e verfasserin |4 aut | |
245 | 1 | 0 | |a PD-1 signaling uncovers a pathogenic subset of T cells in inflammatory arthritis |
264 | 1 | |c 2023 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a ƒaComputermedien |b c |2 rdamedia | ||
338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
500 | |a Date Revised 26.02.2024 | ||
500 | |a published: Electronic | ||
500 | |a UpdateIn: Arthritis Res Ther. 2024 Jan 22;26(1):32. - PMID 38254179 | ||
500 | |a Citation Status PubMed-not-MEDLINE | ||
520 | |a 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. Paired to that, and despite a decade of research, approaches to treat autoimmunity with PD-1 agonists still need to be more successful. To resolve this, new methods must be developed to augment PD-1 function beyond engaging the receptor | ||
520 | |a 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 | ||
520 | |a Results: Our screen confirmed known regulators in proximal PD-1 signaling and, importantly, found an additional 1,112 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 more 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. Back-gating these genes to canonical cytotoxic T cell signatures revealed PD-1 + HLA-DR HIGH KLRG LOW T cells as a novel inflammatory subset of T cells | ||
520 | |a Conclusion: We concluded that PD-1 + HLA-DR HIGH KLRG 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 | ||
650 | 4 | |a Preprint | |
700 | 1 | |a Bukhari, Shoiab |e verfasserin |4 aut | |
700 | 1 | |a Lerrer, Shalom |e verfasserin |4 aut | |
700 | 1 | |a Winchester, Robert |e verfasserin |4 aut | |
700 | 1 | |a Henick, Brian |e verfasserin |4 aut | |
700 | 1 | |a Dragovich, Matthew |e verfasserin |4 aut | |
700 | 1 | |a Mor, Adam |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t bioRxiv : the preprint server for biology |d 2020 |g (2023) vom: 17. Nov. |w (DE-627)NLM31090014X |7 nnns |
773 | 1 | 8 | |g year:2023 |g day:17 |g month:11 |
856 | 4 | 0 | |u http://dx.doi.org/10.1101/2023.11.16.566893 |3 Volltext |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_NLM | ||
951 | |a AR | ||
952 | |j 2023 |b 17 |c 11 |