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Peer-reviewedCC BY-NC 4.0Arthritis & Rheumatology (Hoboken, N.j.)

T Cell Plasticity in Systemic Lupus Erythematosus Revealed by Large‐Scale T Cell Receptor Repertoire and Transcriptome Studies

  • Yasuo Nagafuchi1,2,3,4
  • Masahiro Nakano3
  • Kaitlyn A. Lagattuta5,6,7,8,9
  • Mineto Ota1,2
  • Hiroaki Hatano3,10
  • Haruka Takahashi3,10
  • Takahiro Itamiya1,2,3
  • Hajime Inokuchi3,11
  • Soumya Raychaudhuri5,6,7,8,9
  • Tomohisa Okamura1,2
  • Keishi Fujio1
  • Kazuyoshi Ishigaki3,10,12
12 affiliations
  1. 1Department of Allergy and Rheumatology, Graduate School of Medicine The University of Tokyo Tokyo Japan
  2. 2Department of Functional Genomics and Immunological Diseases, Graduate School of Medicine The University of Tokyo Tokyo Japan
  3. 3Laboratory for Human Immunogenetics, Center for Integrative Medical Sciences RIKEN Kanagawa Japan
  4. 4Division of Rheumatology and Clinical Immunology, Department of Medicine Jichi Medical University Tochigi Japan
  5. 5Center for Data Sciences Brigham and Women's Hospital and Harvard Medical School Boston Massachusetts
  6. 6Division of Genetics, Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston Massachusetts
  7. 7Division of Rheumatology, Inflammation, and Immunity, Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston Massachusetts
  8. 8Program in Medical and Population Genetics Broad Institute of MIT and Harvard Cambridge Massachusetts
  9. 9Department of Biomedical Informatics Harvard Medical School Boston Massachusetts
  10. 10Department of Microbiology and Immunology Keio University School of Medicine Tokyo Japan
  11. 11Division of Rheumatology, Department of Internal Medicine Keio University School of Medicine Tokyo Japan
  12. 12Keio University Human Biology‐Microbiome‐Quantum Research Center Tokyo Japan
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Abstract

Objective: We aimed to characterize CD4+ T cell plasticity in human systemic lupus erythematosus (SLE) by leveraging T cell receptor (TCR) repertoire features as markers of prior lineage states, integrating TCR and transcriptomic profiling to delineate plasticity patterns and evaluate their association with clinical disease activity.

Methods: We used TCR repertoire data as molecular signatures alongside a transcriptomic data set. Using a large‐scale ImmuNexUT database of patients with autoimmune disease, including 117 with SLE, we quantified T cell plasticity across 13 fine‐grained T cell types. We analyzed 6,392 samples in total. We defined “cell type” and “disease” signatures and evaluated plasticity by correlations between these signatures and by within‐donor TCR clonotype overlap. Replication was performed in independent bulk and single‐cell cohorts.

Results: We identified two orthogonal signatures of the repertoire and transcriptome, the cell type and disease signatures, allowing us to investigate CD4+ T cell plasticity comprehensively. Among all possible patterns, the strongest signal was observed between effector Treg cells (eTreg cells) and Th1 cells, and this was replicated in an independent cohort. SLE Th1 cells exhibited Treg‐like TCR features and transcriptomic profiles, and eTreg cells showed increased clonotype sharing with Th1 cells compared with healthy controls. The Th1 “Tregness” score positively correlated with SLE disease activity.

Conclusion: Our study identifies a Treg‐associated Th1 state in human SLE, consistent with Treg cell to Th1 cell plasticity.

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Cite

BibTeXRIS
BibTeX
@article{nagafuchi2026cell,
  title = {{T Cell Plasticity in Systemic Lupus Erythematosus Revealed by Large‐Scale T Cell Receptor Repertoire and Transcriptome Studies}},
  author = {Yasuo Nagafuchi and Masahiro Nakano and Kaitlyn A. Lagattuta and Mineto Ota and Hiroaki Hatano and Haruka Takahashi and Takahiro Itamiya and Hajime Inokuchi and Soumya Raychaudhuri and Tomohisa Okamura and Keishi Fujio and Kazuyoshi Ishigaki},
  journal = {Arthritis \& Rheumatology (Hoboken, N.j.)},
  year = {2026},
  month = jun,
  doi = {10.1002/art.70218},
  url = {https://doi.org/10.1002/art.70218},
  note = {CC BY-NC 4.0},
}
RIS
TY  - JOUR
TI  - T Cell Plasticity in Systemic Lupus Erythematosus Revealed by Large‐Scale T Cell Receptor Repertoire and Transcriptome Studies
AU  - Yasuo Nagafuchi
AU  - Masahiro Nakano
AU  - Kaitlyn A. Lagattuta
AU  - Mineto Ota
AU  - Hiroaki Hatano
AU  - Haruka Takahashi
AU  - Takahiro Itamiya
AU  - Hajime Inokuchi
AU  - Soumya Raychaudhuri
AU  - Tomohisa Okamura
AU  - Keishi Fujio
AU  - Kazuyoshi Ishigaki
PY  - 2026
DA  - 2026/06/02
JO  - Arthritis & Rheumatology (Hoboken, N.j.)
DO  - 10.1002/art.70218
UR  - https://doi.org/10.1002/art.70218
AB  - Objective: We aimed to characterize CD4+ T cell plasticity in human systemic lupus erythematosus (SLE) by leveraging T cell receptor (TCR) repertoire features as markers of prior lineage states, integrating TCR and transcriptomic profiling to delineate plasticity patterns and evaluate their association with clinical disease activity.  Methods: We used TCR repertoire data as molecular signatures alongside a transcriptomic data set. Using a large‐scale ImmuNexUT database of patients with autoimmune disease, including 117 with SLE, we quantified T cell plasticity across 13 fine‐grained T cell types. We analyzed 6,392 samples in total. We defined “cell type” and “disease” signatures and evaluated plasticity by correlations between these signatures and by within‐donor TCR clonotype overlap. Replication was performed in independent bulk and single‐cell cohorts.  Results: We identified two orthogonal signatures of the repertoire and transcriptome, the cell type and disease signatures, allowing us to investigate CD4+ T cell plasticity comprehensively. Among all possible patterns, the strongest signal was observed between effector Treg cells (eTreg cells) and Th1 cells, and this was replicated in an independent cohort. SLE Th1 cells exhibited Treg‐like TCR features and transcriptomic profiles, and eTreg cells showed increased clonotype sharing with Th1 cells compared with healthy controls. The Th1 “Tregness” score positively correlated with SLE disease activity.  Conclusion: Our study identifies a Treg‐associated Th1 state in human SLE, consistent with Treg cell to Th1 cell plasticity.
SN  - 2326-5191
SN  - 2326-5205
ER  -