ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 0980

Expansion of Viral-Reactive CD8+ T cell Repertoire Stratified by Pathotype in New-onset ACPA+ Rheumatoid Arthritis

Carl Coyle1, Wittaya Suwakulsiri2, Lukas Andriessen3, Megan Soon4, Pascale Wehr5, Sumera Qureshi6, Christopher Altmann7, Annabelle Small8, Vincent Wong9, Andrew Cope6, Kevin Wei10, Hendrik Nel5, Mihir Wechalekar11 and Ranjeny Thomas2, 1Kings College London, London, United Kingdom, 2Frazer Institute, University of Queensland, Brisbane, Queensland, Australia, 3Frazer Institute, University of Queensland, Woolloongabba, Queensland, Australia, 4Frazer Institute, The University of Queensland, Brisbane, Australia, 5University of Queensland, Woolloongabba, Queensland, Australia, 6King's College London, London, United Kingdom, 7Flinders University, Adelaide, Australia, 8Flinders University, Bedford Park, South Australia, Australia, 9College of Medicine and Public Health, Bedford Park, South Australia, Australia, 10Brigham and Women's Hospital at Harvard Medical School, Boston, MA, 11Flinders Medical Centre, Adelaide, Australia

Meeting: ACR Convergence 2025

Keywords: , , ,

Session Information

Date: Monday, October 27, 2025

Title: (0978–1006) T Cell Biology & Targets in Autoimmune & Inflammatory Disease Poster

Session Type: Poster Session B

Session Time: 10:30AM-12:30PM

Background/Purpose: Development of Rheumatoid Arthritis (RA) is strongly associated with specific HLA-DRB1 genotypes and the HLA-DR antigen binding groove, the shared epitope. HLA-B*08 also increases risk of ACPA+ RA, and large numbers of CD8+, including granzyme K (GZMK)+ tissue-resident T cells (Trm), infiltrate RA synovial tissue (ST) in active, established RA. ST from DMARD-naïve patients can be classified into lymphomyeloid (LM), diffuse myeloid (DM) or pauci-immune (PI) “pathotypes”. While most T cell receptor (TCR) repertoire analysis focused on highly inflamed LM ST, TCR repertoires of DM and PI ST are poorly characterized.

Methods: We compared CD45+ antigen-presenting cells (APCs) and TCR repertoire in arthroscopic ST and paired peripheral blood (PB) from 9 recent-onset DMARD-naïve ACPA+ DM- or PI-pathotype RA patients with symptom duration up to 1 year, using single-cell(sc) RNA/TCR-sequencing (all except one HLA-DRB1*04:01 shared-epitope+). ST biopsies from 9 ACPA+ DM and 10 PI pathotyped RA patients were imaged using spatial transcriptomic profiling (5,101 genes, 10x Genomics).

Results: scRNAseq identified PB classical and non-classical monocytes, dendritic cells (DCs). In ST, myeloid DCs and macrophages were enriched in APC and lymphocyte-activation genes. In PI pathotype PB non-classical monocytes, ST myeloid DCs and macrophages were reduced compared to DM pathotype. CD4+ T cells had limited clonal expansion. The repertoire included public non-expanded viral-reactive clonotypes. Most memory CD8+ T cells expressed GZMB, GRZK or both. GZMK+GZMB+/- CD8+ T cell clones were moderately expanded and expressed Trm markers in ST, while GZMB+GZMK- CD8 clones were highly-expanded in PB. Grouping of lymphocyte interactions by paratope hotspots (GLIPH) identified cytomegalovirus (CMV) and Epstein-Barr virus (EBV)-reactive TCRs, which were GZMB+ in PB, and often shared in ST as GZMK+ Trm. CMV-reactive clonal expansion occurred in DM and PI pathotypes, restricted by HLA-A*02:01 and HLA-A*03:01 evenly across pathotypes. In contrast, EBV-reactive clonal expansion (GZMK+, HLA-B*08-restricted) was highly-enriched in the PI pathotype. Xenium spatial imaging in DM and PA ST identified small numbers of infiltrating GZMB+GZMK+/- CD8+ T cells and rare plasma cells. Besides larger macrophage infiltrates and expanded lining fibroblasts, PI T-cell infiltrates in DM were distinguished from PI pathotype by adjacent Clec9A+ DCs or type 1 interferon-induced CXCL11.

Conclusion: The data suggest strong CD8+ PB clonal expansion towards latent viruses and bystander ST infiltration in early ACPA+ RA of both pathotypes, but with HLA-B*08-restriction skewed to EBV-reactive Trm in PI. MHC class I genes may shape the CD8+ Trm repertoire, viral antigen presentation and ST pathology in RA.

Disclosures: C. Coyle: None; W. Suwakulsiri: None; L. Andriessen: None; M. Soon: None; P. Wehr: None; S. Qureshi: Bristol-Myers Squibb(BMS), 5; C. Altmann: None; A. Small: None; V. Wong: None; A. Cope: Bristol-Myers Squibb(BMS), 2, 5, 6; K. Wei: 10X Genomics, 5, anaptysbio, 2, Gilead, 5, Merck/MSD, 5, Mestag, 2, Pfizer, 2; H. Nel: None; M. Wechalekar: GlaxoSmithKlein(GSK), 5, Janssen, 5; R. Thomas: AbbVie/Abbott, 2, CSL, 2.

To cite this abstract in AMA style:

Coyle C, Suwakulsiri W, Andriessen L, Soon M, Wehr P, Qureshi S, Altmann C, Small A, Wong V, Cope A, Wei K, Nel H, Wechalekar M, Thomas R. Expansion of Viral-Reactive CD8+ T cell Repertoire Stratified by Pathotype in New-onset ACPA+ Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2025; 77 (suppl 9). https://acrabstracts.org/abstract/expansion-of-viral-reactive-cd8-t-cell-repertoire-stratified-by-pathotype-in-new-onset-acpa-rheumatoid-arthritis/. Accessed .

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