Exploratory single-cell multiomics suggests naive CD4+ T cell dysregulation in treatment refractory rheumatoid arthritis
Abstract
Around 20% of patients with rheumatoid arthritis (RA) have disease that remains refractory to multiple targeted treatments, highlighting a major clinical challenge. We determine single-nucleus transcriptional and chromatin landscapes (10x Genomics Epi Multiome) on 14,625 primary CD4+ T-cells isolated from treatment-naive early and refractory (defined as per the EULAR definition of difficult-to-treat) patients with RA. We systematically analyze circulating regulatory profiles to reveal potential mechanisms and therapeutic targets that may contribute to the difficult-to-treat phenotype. We highlight disease-stage-specific alterations in naive and Th1-like memory CD4+ T-cells. In particular, refractory naive cells show signatures of heightened activation, upregulation of pathways aligning with T cell anergy, diminished regulation at regulatory loci (e.g., FOXP1, ICOS) and blunted stimulation responses; consistent with a more desensitized or exhausted state. Genes such as LGALS3, ZBTB7B and FOXO4 emerge as potential candidate regulators of the difficult-to-treat state. Finally, through RA GWAS integration, we prioritize putative causal variants in cis-regulatory elements.
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BibTeX
@article{smith2026exploratory,
title = {{Exploratory single-cell multiomics suggests naive CD4+ T cell dysregulation in treatment refractory rheumatoid arthritis}},
author = {Samantha L. Smith and Stefano Rossi and Rudresh Shukla and Chuan Fu Yap and Nisha Nair and Jake Butler and Yvonne Tan and Amirah Binti Mohammad Ariff and Ilinca Lazar and Khadijah Patel and Stephen Eyre and Maya H. Buch and Paul Martin and Gisela Orozco},
journal = {iScience},
year = {2026},
month = oct,
doi = {10.1016/j.isci.2026.117949},
url = {https://www.cell.com/iscience/fulltext/S2589-0042(26)03332-8},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Exploratory single-cell multiomics suggests naive CD4+ T cell dysregulation in treatment refractory rheumatoid arthritis
AU - Samantha L. Smith
AU - Stefano Rossi
AU - Rudresh Shukla
AU - Chuan Fu Yap
AU - Nisha Nair
AU - Jake Butler
AU - Yvonne Tan
AU - Amirah Binti Mohammad Ariff
AU - Ilinca Lazar
AU - Khadijah Patel
AU - Stephen Eyre
AU - Maya H. Buch
AU - Paul Martin
AU - Gisela Orozco
PY - 2026
DA - 2026/10/26
JO - iScience
DO - 10.1016/j.isci.2026.117949
UR - https://www.cell.com/iscience/fulltext/S2589-0042(26)03332-8
AB - Around 20% of patients with rheumatoid arthritis (RA) have disease that remains refractory to multiple targeted treatments, highlighting a major clinical challenge. We determine single-nucleus transcriptional and chromatin landscapes (10x Genomics Epi Multiome) on 14,625 primary CD4+ T-cells isolated from treatment-naive early and refractory (defined as per the EULAR definition of difficult-to-treat) patients with RA. We systematically analyze circulating regulatory profiles to reveal potential mechanisms and therapeutic targets that may contribute to the difficult-to-treat phenotype. We highlight disease-stage-specific alterations in naive and Th1-like memory CD4+ T-cells. In particular, refractory naive cells show signatures of heightened activation, upregulation of pathways aligning with T cell anergy, diminished regulation at regulatory loci (e.g., FOXP1, ICOS) and blunted stimulation responses; consistent with a more desensitized or exhausted state. Genes such as LGALS3, ZBTB7B and FOXO4 emerge as potential candidate regulators of the difficult-to-treat state. Finally, through RA GWAS integration, we prioritize putative causal variants in cis-regulatory elements.
SN - 2589-0042
ER -