Antigen‐driven PD‐1+TOX+BHLHE40+ and PD‐1+TOX+EOMES+ T lymphocytes regulate juvenile idiopathic arthritis in situ

Maschmeyer, Patrick; Heinz, Gitta Anne; Skopnik, Christopher Mark; Lutter, Lisanne; Mazzoni, Alessio; Heinrich, Frederik; Stuckrad, Anne Sae Lim von; Wirth, Lorenz Elias; Tran, Cam Loan; Riedel, René; Lehmann, Katrin; Sakwa, Imme; Cimaz, Rolando; Giudici, Francesco; Mall, Marcus; Enghard, Philipp; Vastert, Bas; Chang, Hyun‐Dong; Durek, Pawel; Annunziato, Francesco; Wijk, Femke van; Radbruch, Andreas; Kallinich, Tilmann; Mashreghi, Mir‐Farzin

doi:10.1002/eji.202048797

Cited by 26 publications

(29 citation statements)

References 86 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…CD4 T cells separated into six clusters, the largest of which was a central memory‐like cluster ( CCR7 , SELL ), similar to findings from RA and PsA samples ( 16 , 28 , 41 ). The next largest cluster appeared as a Tph cluster, with high expression of PDCD1 , IL21 , CXCL13 , ENTPD1 , and CD40LG , as well as increased expression of cytokines CSF2 (encoding GM‐CSF), TNF, and IFNG.…”

Section: High‐dimensional Views Of T‐cell Infiltrates In Rheumatic Diseasessupporting

confidence: 75%

“…A second highly activated cluster displayed a different set of functional properties, characterized by high expression of IL10 , PRF1 , GZMK , and the transcription factor EOMES. This cluster of CD4 T cells was also present in peripheral blood from patients with JIA, as indicated by an overlap in both T‐cell receptor (TCR) repertoire and expression of cytotoxicity‐associated genes ( 41 ).…”

Section: High‐dimensional Views Of T‐cell Infiltrates In Rheumatic Diseasesmentioning

confidence: 99%

“…scRNA‐seq analysis of synovial fluid T cells from seven patients with oligoarticular juvenile idiopathic arthritis (JIA) was recently reported ( 41 ). T cells were flow cytometrically sorted, and 74 891 scRNA‐seq transcriptomes were generated by the 10X Genomics platform.…”

Section: High‐dimensional Views Of T‐cell Infiltrates In Rheumatic Diseasesmentioning

confidence: 99%

“…The next largest cluster appeared as a Tph cluster, with high expression of PDCD1 , IL21 , CXCL13 , ENTPD1 , and CD40LG , as well as increased expression of cytokines CSF2 (encoding GM‐CSF), TNF, and IFNG. These cells lacked CXCR5 at the mRNA and protein level and instead expressed transcriptomic signatures of peripheral tissue localization, including expression of the chemokine receptor CXCR6 ( 41 ). A second highly activated cluster displayed a different set of functional properties, characterized by high expression of IL10 , PRF1 , GZMK , and the transcription factor EOMES.…”

Section: High‐dimensional Views Of T‐cell Infiltrates In Rheumatic Diseasesmentioning

confidence: 99%

“…In addition, a cluster with increased expression of Th17‐associated genes RORC , IL23R , and CCR6 was also identified and comprised 13% of the synovial fluid CD4 T cells ( 41 ). Although comparisons across studies are limited by technical and data processing differences, these cells appear roughly similar to the Th17 cluster identified in PsA samples ( 28 ).…”

Section: High‐dimensional Views Of T‐cell Infiltrates In Rheumatic Diseasesmentioning

confidence: 99%

See 4 more Smart Citations

Patterns of T‐Cell Phenotypes in Rheumatic Diseases From Single‐Cell Studies of Tissue

Gao

Dunlap

Elahee

et al. 2021

ACR Open Rheumatology

View full text Add to dashboard Cite

High‐dimensional analyses of tissue samples from patients with rheumatic diseases are providing increasingly detailed descriptions of the immune cell populations that infiltrate tissues in different rheumatic diseases. Here we review key observations emerging from high‐dimensional analyses of T cells within tissues in different rheumatic diseases, highlighting common themes across diseases as well as distinguishing features. Single‐cell RNA sequencing analyses capture several dimensions of T‐cell states, yet surprisingly, these analyses generally have not demonstrated distinct clusters of paradigmatic T‐cell effector subsets, such as T helper (Th) 1, Th2, and Th17 cells. Rather, global transcriptomics robustly identify both proliferating T cells and regulatory T cells and have also helped to reveal new effector subsets in inflamed tissues, including T peripheral helper cells and granzyme K+ T cells. Further characterization of the T‐cell populations that accumulate within target tissues should enable more precise targeting of biologic therapies and accelerate development of more specific biomarkers to track activity of relevant immune pathways in patients with rheumatic diseases.

show abstract

Section: High‐dimensional Views Of T‐cell Infiltrates In Rheumatic Diseasessupporting

confidence: 75%

Section: High‐dimensional Views Of T‐cell Infiltrates In Rheumatic Diseasesmentioning

confidence: 99%

Section: High‐dimensional Views Of T‐cell Infiltrates In Rheumatic Diseasesmentioning

confidence: 99%

Section: High‐dimensional Views Of T‐cell Infiltrates In Rheumatic Diseasesmentioning

confidence: 99%

Section: High‐dimensional Views Of T‐cell Infiltrates In Rheumatic Diseasesmentioning

confidence: 99%

See 3 more Smart Citations

Patterns of T‐Cell Phenotypes in Rheumatic Diseases From Single‐Cell Studies of Tissue

Gao

Dunlap

Elahee

et al. 2021

ACR Open Rheumatology

View full text Add to dashboard Cite

show abstract

Human regulatory T cells locally differentiate and are functionally heterogeneous within the inflamed arthritic joint

et al. 2022

Self Cite

View full text Add to dashboard Cite

Objective Tregs are crucial for immune regulation, and environment‐driven adaptation of effector (e)Tregs is essential for local functioning. However, the extent of human Treg heterogeneity in inflammatory settings is unclear. Methods We combined single‐cell RNA‐ and TCR‐sequencing on Tregs derived from three to six patients with juvenile idiopathic arthritis (JIA) to investigate the functional heterogeneity of human synovial fluid (SF)‐derived Tregs from inflamed joints. Confirmation and suppressive function of the identified Treg clusters was assessed by flow cytometry. Results Four Treg clusters were identified; incoming, activated eTregs with either a dominant suppressive or cytotoxic profile, and GPR56 + CD161 + CXCL13 + Tregs. Pseudotime analysis showed differentiation towards either classical eTreg profiles or GPR56 + CD161 + CXCL13 + Tregs supported by TCR data. Despite its most differentiated phenotype, GPR56 + CD161 + CXCL13 + Tregs were shown to be suppressive. Furthermore, BATF was identified as an overarching eTreg regulator, with the novel Treg‐associated regulon BHLHE40 driving differentiation towards GPR56 + CD161 + CXCL13 + Tregs, and JAZF1 towards classical eTregs. Conclusion Our study reveals a heterogeneous population of Tregs at the site of inflammation in JIA. SF Treg differentiate to a classical eTreg profile with a more dominant suppressive or cytotoxic profile that share a similar TCR repertoire, or towards GPR56 + CD161 + CXCL13 + Tregs with a more distinct TCR repertoire. Genes characterising GPR56 + CD161 + CXCL13 + Tregs were also mirrored in other T‐cell subsets in both the tumor and the autoimmune setting. Finally, the identified key regulators driving SF Treg adaptation may be interesting targets for autoimmunity or tumor interventions.

show abstract

Clonally expanded PD‐1‐expressing T cells are enriched in synovial fluid of juvenile idiopathic arthritis patients

et al. 2023

Self Cite

View full text Add to dashboard Cite

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic condition in childhood. The disease etiology remains largely unknown; however, a key role in JIA pathogenesis is surely mediated by T cells. T‐lymphocytes activity is controlled via signals, known as immune checkpoints. Delivering an inhibitory signal or blocking a stimulatory signal to achieve immune suppression is critical in autoimmune diseases. However, the role of immune checkpoints in chronic inflammation and autoimmunity must still be deciphered. In this study, we investigated at the single‐cell level the feature of T cells in JIA chronic inflammation, both at the transcriptome level via single‐cell RNA sequencing and at the protein level by flow cytometry. We found that despite the heterogeneity in the composition of synovial CD4+ and CD8+ T cells, those characterized by PD‐1 expression were clonally expanded tissue‐resident memory (Trm)‐like cells and displayed the highest proinflammatory capacity, suggesting their active contribution in sustaining chronic inflammation in situ. Our data support the concept that novel therapeutic strategies targeting PD‐1 may be effective in the treatment of JIA. With this approach, it may become possible to target overactive T cells regardless of their cytokine production profile.

show abstract

Antigen‐driven PD‐1⁺TOX⁺BHLHE40⁺ and PD‐1⁺TOX⁺EOMES⁺ T lymphocytes regulate juvenile idiopathic arthritis in situ

Cited by 26 publications

References 86 publications

Patterns of T‐Cell Phenotypes in Rheumatic Diseases From Single‐Cell Studies of Tissue

Patterns of T‐Cell Phenotypes in Rheumatic Diseases From Single‐Cell Studies of Tissue

Human regulatory T cells locally differentiate and are functionally heterogeneous within the inflamed arthritic joint

Clonally expanded PD‐1‐expressing T cells are enriched in synovial fluid of juvenile idiopathic arthritis patients

Contact Info

Product

Resources

About