What question did this study set out to answer?

To characterize CD8+ T cell clonality in anti-CCP+ at-risk individuals and assess its link to inflammatory arthritis progression.

April 30, 2026

OA37 The emergence of clonally expanded cytotoxic CD8+ T Cells accompanies subclinical synovitis and precedes the development of clinical arthritis in anti-CCP+ at-risk individuals

Key Points

To characterize CD8+ T cell clonality in anti-CCP+ at-risk individuals and assess its link to inflammatory arthritis progression.
Analyzed peripheral blood from 45 donors including 40 anti-CCP+ individuals without clinical synovitis and 5 healthy controls.
Used ultrasound to assess joint inflammation and scRNA-seq to profile T cell clonality and diversity.
Clonotypes were classified based on size, and statistical analyses were performed using Wilcoxon or Kruskal-Wallis tests.
22 of the 45 donors developed inflammatory arthritis, with some showing ultrasound positivity at baseline.
CD8+ T cells exhibited greater clonal expansion compared to CD4+ T and B cells, significantly increased in ultrasound-positive progressors.
Unsupervised clustering revealed five distinct CD8+ T cell clusters, with specific clusters linked to cytotoxic signatures and elevated in ultrasound-positive individuals.

Abstract

Abstract Background/Aims High anti-CCP titres predict inflammatory arthritis (IA) development, indicating loss of tolerance to citrullinated antigens. Clonally expanded CD8-T cells recognising citrullinated autoantigens via MHC-I have been identified in CCP+ RA. We investigated whether such expansions occur preclinically by characterising circulating CD8+ T cell clonality in anti-CCP+ at-risk individuals using scRNA-seq and assessing links with IA progression. Methods Peripheral blood from 45 donors (5 healthy controls, 40 anti-CCP+ at-risk without clinical synovitis) was analysed. Ultrasound (US) assessed 36 joints; US-positive was power Doppler ≥ 1 and greyscale ≥ 1; IA = ≥ 1 swollen joint confirmed clinically. Paired scRNA-seq and TCR/BCR data were processed in Seurat (log-normalisation, 2,000 variable genes, 30 PCs, UMAP, Louvain clustering 0.1). Clonotypes (TRB CDR3 + V/J usage) were classed as singleton (1), small (2-4), medium (5-19), large (≥ 20). Clonality and clone size distributions were compared across cell types (CD8, CD4, B) and clinical groups. Statistics: Wilcoxon or Kruskal-Wallis with BH-FDR correction. Results Among 45 donors, 22 developed IA, half of whom were US-pos at baseline. CD8+ T cells showed significantly greater clonal expansion than CD4+ T or B cells, with clonality markedly elevated in US-pos progressors (p 0.001) and enriched for medium and large clones. CD4+ and B cell clonality remained uniformly low across groups. Unsupervised clustering identified five CD8+ T cell clusters; US-pos status was linked to increased cluster 2, emergence of cluster 5, and reduction in clusters 1 and 3. Clusters 2 and 5 exhibited dominant cytotoxic signatures (GZMB, GNLY, NKG7), with US-pos group had more GZMK+ and GNLY+ cells, with large clones being the main contributors. Large CD8+ clones were enriched for cytotoxic effectors and the tissue residency factor ZNF683, suggesting migration to and persistence in inflamed joints. Conclusion In anti-CCP+ at-risk individuals, cytotoxic CD8+ clonal expansions arise after subclinical synovitis, suggesting a late effector role and potential therapeutic target in arthritis progression. Disclosure K. Abacar: None. F. Tariq: None. P. Martin: None. W. Ye: None. X. Sun: None. S. Mackay: None. D. Muldoon: None. L. Duquenne: None. A. Di Matteo: None. K. Harnden: None. K. Mbara: None. M. Menon: None. M.H. Buch: None. H. Al-Mosawi: Other; working in Astrazeneca. B. Fairfax: None. P. Emery: Other; AbbVie, BMS, Pfizer, MSD, Roche, Janssen, Novartis, and UCB. D. Newton: None. K. Mankia: Other; AbbVie, ALLin Bio, AstraZeneca, UCB, Eli Lilly, Galapagos, Serac Healthcare, Zura Bio, Deepcure, and Gilead.

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Cite This Study

Abacar et al. (Wed,) studied this question.

synapsesocial.com/papers/69f2a47b8c0f03fd677638b7 https://doi.org/https://doi.org/10.1093/rheumatology/keag121.031

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