CD4+ tissue-resident memory Th17 cells are a major source of IL-17A in Spondyloarthritis synovial tissue
Notice bibliographique
Résumé
Abstract Objectives Interleukin (IL)-17A is a key driver of Spondyloarthritis (SpA) joint pathology. We aimed to identify its cellular source in synovial tissue from patients with two forms of SpA namely Axial SpA (AxSpA) and Psoriatic arthritis (PsA). Methods Synovial tissue from patients with SpA was profiled using single-cell RNA sequencing (scRNA-seq: AxSpA, n=5 and PsA, n=6) or spatial RNA profiling (PsA, n=4). CellPhoneDB was used to infer cell–cell communication. Tissue resident memory Th17 (TRM17)-like cells were generated in vitro using blood memory CD4+ T cells from SpA patients. An epigenetic inhibitor library, siRNA and clustered regularly interspaced short palindromic repeats (CRISPR) were used to identify epigenetic regulator(s) for TRM17. Results scRNA-seq showed that CD4+CXCR6+ TRM17 cells are the predominant spontaneous IL17A producers in SpA synovium. Cell-cell communication and single-cell spatial analysis support the interaction between TRM17 and CLEC10A+ dendritic cells, which were activated in SpA. Both sublining and lining fibroblasts in SpA synovium showed evidence of IL-17A activation. In vitro-generated CD4+ TRM17-like cells phenocopied joint tissue TRM17, producing IL-17A/F upon T cell receptor (TCR) stimulation, which was further enhanced by cytokines. Perturbation of BRD1 inhibited the generation of TRM17-like cells. Conclusions CD4+ TRM17 cells are the predominant source of IL-17A in SpA synovial tissue. TCR stimulation is essential for the secretion of IL-17A by CD4+TRM17-like cells. The epigenetic regulator BRD1 contributes to the generation of CD4+TRM17. Depleting CD4+TRM17 cells in SpA is thus a therapeutic strategy with potential to induce long-term remission. Key messages What is already known on this topic Interleukin (IL)-17A plays a key role in the immunopathogenesis of Spondyloarthritis (SpA), but its cellular source in joint tissue has not been determined previously. The induction and accumulation of CD4+ tissue resident memory Th17 (TRM17) cells following the clearance of pathogens has been described in skin, lung and kidney. Whether CD4+ TRM17 cells also accumulate in the joint and contribute to the pathology of SpA is not clear. What this study adds CD4+ TRM17 cells are present in SpA synovial tissue and are the predominant source of IL17A CD4+ TRM17 cells in SpA joints express IL17A without any in vitro exogenous stimulation T cell receptor (TCR) rather than cytokine stimulation is essential for IL-17A production by CD4+ TRM17-like cells The epigenetic regulator BRD1 contributes to the generation of CD4+ TRM17-like cells. How this study might affect research, practice or policy Our findings identify CD4+ TRM17 cells as the primary source of IL-17A in SpA synovium, a previously unrecognized role for these cells. Key questions remain: How do CD4+ TRM17 cells relate to IL-17A producers in synovial fluid? What mechanisms induce and maintain them in the joint? How do they interact with other cells to promote arthritis? These questions warrant further investigation. In addition, our data suggest that targeting CD4+ TRM17 cells, the “factory” of IL-17A in SpA synovial tissue, has the potential to induce long-term remission, encouraging future efforts to develop new therapies to deplete CD4+ TRM17 cells in SpA.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,004 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».