Epigenetic control of pathogenic CD4 T cell polarization during progression to rheumatoid arthritis 3989

Abstract Description T cells contribute to the pathology associated with rheumatoid arthritis (RA). While T cell co-stimulation modulation with Abatacept (CTLA4-lg) has shown promise in delaying RA onset, the mechanisms driving T cell-mediated progression from pre-disease to active RA remain unclear. We conducted longitudinal scRNA-seq profiling of PBMCs from 45 ACPA+ individuals at risk for RA (ARI), 16 of whom later developed clinical RA (converters) and performed trimodal single cell assay TEA-Seq in a subset of ARI (n = 7) and ACPA- controls (n = 5). We observed extensive transcriptomic changes in CD4 naive and memory cells and an expansion of Tfh17 (PDCD1+CXCR5+KLRB1+RORA+) cells during progression to clinical RA. Trimodal integration revealed upregulation of genes in the calcium–calcineurin–NFAT pathway, enrichment of NFAT motifs, and increased accessibility in an enhancer region of IL21 in the ARI naive CD4 T cells. Our findings indicate that effector CD4 T programs in the converters were biased towards Tph17 development during progression to RA. Additionally, ARI CD4 naive cells exhibited an activation state, with epigenetic imprints linked to Tfh development. Overall, these results suggest that activation and epigenetic reprogramming of naive cells may contribute to specific bias in effector T cell programs during progression to RA disease, providing mechanistic insights for targeting T cells during an at-risk period to potentially prevent or delay clinical RA. Funding Sources This work was supported by the Allen Institute. Topic Categories Basic Autoimmunity (BA)

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Publication Details

Journal
The Journal of Immunology
Published
2025-11-01
DOI
https://doi.org/10.1093/jimmun/vkaf283.1726
Primary Topic
Signaling Pathways in Disease
Type
article
Field-Weighted Citation Impact
0.00

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article

Epigenetic control of pathogenic CD4 T cell polarization during progression to rheumatoid arthritis 3989

Kevin D. Deane, Thomas F. Bumol, Jane H. Buckner, Gary S. Firestein et al.
The Journal of Immunology
Signaling Pathways in Disease
article

Epigenetic control of pathogenic CD4 T cell polarization during progression to rheumatoid arthritis 3989

Kevin D. Deane, Thomas F. Bumol, Jane H. Buckner, Gary S. Firestein, Padmapriyadarshini Ravisankar, Lauren Okada, Palak C. Genge, Nhung T. T. Tran, Adam K. Savage, CE Bennett, Marla C. Glass, Michael Holers, Pravina Venkatesan, Ziyuan He, Ananda W. Goldrath, Upaasana Krishnan, Troy R. Torgerson, Peter J. Skene, Samir Rachid Zaim, Mark A. Gillespie, Cole Phalen, Marie L. Feser, Jessica Garber, Xiaojun Li, Yudong D. He, Kevin J. Lee, R Mettey
article en

Abstract

Abstract Description T cells contribute to the pathology associated with rheumatoid arthritis (RA). While T cell co-stimulation modulation with Abatacept (CTLA4-lg) has shown promise in delaying RA onset, the mechanisms driving T cell-mediated progression from pre-disease to active RA remain unclear. We conducted longitudinal scRNA-seq profiling of PBMCs from 45 ACPA+ individuals at risk for RA (ARI), 16 of whom later developed clinical RA (converters) and performed trimodal single cell assay TEA-Seq in a subset of ARI (n = 7) and ACPA- controls (n = 5). We observed extensive transcriptomic changes in CD4 naive and memory cells and an expansion of Tfh17 (PDCD1+CXCR5+KLRB1+RORA+) cells during progression to clinical RA. Trimodal integration revealed upregulation of genes in the calcium–calcineurin–NFAT pathway, enrichment of NFAT motifs, and increased accessibility in an enhancer region of IL21 in the ARI naive CD4 T cells. Our findings indicate that effector CD4 T programs in the converters were biased towards Tph17 development during progression to RA. Additionally, ARI CD4 naive cells exhibited an activation state, with epigenetic imprints linked to Tfh development. Overall, these results suggest that activation and epigenetic reprogramming of naive cells may contribute to specific bias in effector T cell programs during progression to RA disease, providing mechanistic insights for targeting T cells during an at-risk period to potentially prevent or delay clinical RA. Funding Sources This work was supported by the Allen Institute. Topic Categories Basic Autoimmunity (BA)

The Journal of ImmunologyVol. 214(Supplement_1)
University of California San Diego (US), Allen Institute for Immunology (US), Benaroya Research Institute, University of Colorado Anschutz Medical Campus (US)
National Institutes of Health, National Institute of Neurological Disorders and Stroke
Openalex Percentile: Top 68%
Signaling Pathways in Disease
DOIOpen Access PDFOpenAlex
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