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Exp. Mol. Med., 01 August 2025 | https://doi.org/10.1038/s12276-025-01504-2 Tracking clonal dynamics of CD8 T cells and immune dysregulation in progression of systemic lupus erythematosus with nephritis

Seung-Jun Paek ^1,2,13, Hye-Soon Lee^3,4,5,13, Ye Ji Lee ^6,13, So-Young Bang^3,4,5, Dongju Kim ⁷, Bo-Kyeong Kang ⁸, Dae Jin Park^3,4, Young Bin Joo ^3,4, Mimi Kim ⁸, Hyunsung Kim ⁹, Sung Yul Park ¹⁰, Woong-Yang Park ^6,11, Tatsuki Abe ¹², Takahiro Itamiya ¹², Yasuo Nagafuchi ¹², Kazuyoshi Ishigaki ¹², Keishi Fujio ¹², Kyu-Tae Kim ^1,2,* and Sang-Cheol Bae ^3,4,5,*

¹Department of Physiology, School of Medicine, Ajou University, Suwon, Republic of Korea.
²Department of Biomedical Sciences, Graduate School of Ajou University, Suwon, Republic of Korea.
³Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Republic of Korea.
⁴Hanyang University Institute for Rheumatology Research, Seoul, Republic of Korea.
⁵Hanyang Institute of Bioscience and Biotechnology, Seoul, Republic of Korea.
⁶GENINUS Inc., Seoul, Republic of Korea.
⁷Department of Translational Medical Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Republic of Korea.
⁸Department of Radiology, College of Medicine, Hanyang University, Seoul, Republic of Korea.
⁹Department of Pathology, College of Medicine, Hanyang University, Seoul, Republic of Korea.
¹⁰Department of Urology, College of Medicine, Hanyang University, Seoul, Republic of Korea.
¹¹Samsung Genome Institute, Samsung Medical Center, School of Medicine, Sungkyunkwan University, Seoul, Republic of Korea.
¹²Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
¹³These authors contributed equally: SeungJun Paek, Hye-Soon Lee, Ye Ji Lee.

^*Corresponding authors: correspondence to Kyu-Tae Kim or Sang-Cheol Bae

Abstract

The fluctuating nature of disease activity in systemic lupus erythematosus (SLE), alternating between flares and remissions, poses substantial challenges for its effective management. The use of current biomarkers for monitoring SLE is limited in clinical settings owing to insufficient comprehension of the complex immune involvement underlying the disease course. Here, therefore, we profiled peripheral blood mononuclear cells at both stable and exacerbation states (total of n = 19) from six patients with SLE and 32 healthy donors using integrated single-cell RNA and T cell receptor (TCR) sequencing. To validate our findings, we analyzed two independent external datasets: bulk RNA sequencing and TCR data from 79 controls and 62 patients with SLE and single-cell RNA sequencing data from 99 healthy controls and 162 patients with SLE. Our analysis revealed cell type-specific activation of interferon-related genes in SLE grouped into four clusters, with elevated activity in disease-associated immune cells. Among these, atypical B cells associated with autoantibody production exhibited distinct differentiation patterns compared with conventional memory B cells, driven by heightened interferon signaling in SLE. Notably, clonal expansion of effector CD8 T cells emerged as a key driver of disease exacerbation, as indicated by reduced TCR diversity. Specific CD8 T cell clonotypes expanded during flare states, transitioning to effector phenotypes that exhibited heightened cytotoxicity and amplified interferon signaling, strongly correlating with tissue damage and flare severity. Our findings establish a critical link between interferon-driven mechanisms and cytotoxic T cell dysfunction in SLE flares, offering potential targets for therapeutic intervention and predictive biomarkers.

논문정보

형식Research article
게재일2025년 08월 (BRIC 등록일 2025-08-01)
연구진국내(교신)+국외 연구진
분야 의약학 > 면역의학

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