In autoimmune disorders, immune cells targeting ‘self’ proteins are mistakenly activated, resulting in their abnormal expansion and responsiveness. It has been known to reduce the quality of life of patients over a prolonged period. This can be attributed to CD4 + T cells that play a key role in inducing persistent inflammation, recruiting other immune cells, including antibody-producing B cells, and inflicting tissue damage. Notably, an autoimmune disorder called primary Sjögren disease (pSjD) is characterized by inflammation in the tear- and saliva-producing glands, and patients experience not only dry mouth and dry eyes but also other systemic complications. This necessitates the development of new therapies that can fundamentally regulate the underlying disease pathology. To this end, it is important to explore the underlying pathology involving subsets of pathogenic CD4 + T cells and their non-immune cell partners.
To bridge this knowledge gap, a team of researchers led by Professor Koji Yasutomo from the Department of Immunology and Parasitology, Graduate School of Medicine, Tokushima University, Japan, who is also a Distinguished Professor and the Chief Research Officer at the Institute of Photonics and Human Health Frontier, also at Tokushima University, and Assistant Professor Kunihiro Otsuka from the Department of Oral and Maxillofacial Surgery, Tokushima University Hospital, Japan, reveal that in addition to the overzealous CD4 + T cells, the non-immune fibroblasts (structural cells that make up the tissue) are actively involved in the progression of the autoimmune disease. Their findings were published in Nature Communications on May 12, 2026.
“We have long been interested in understanding the characteristics of T cells involved in the onset and progression of autoimmune diseases. While tissues affected in Sjögren disease not only accumulate immune cells but also form lymphoid-like tissue aggregates, the roles played by non-immune tissue-resident cells are poorly understood,” explains Prof. Yasutomo while sharing their motivation for this study.
Seeking answers to these gaps in understanding, the researchers employed a mouse model of pSjD. They performed high-resolution single-cell RNA sequencing and T cell receptor sequencing on cells from the salivary glands of the mouse model. Notably, CD4 + T cells expressing CD153 directly interact with CD30-expressing fibroblasts, promoting fibroblast activation, proliferation, and the production of inflammatory chemokines, which are proteins that act as chemical signals to guide the movement of immune cells. Further, the CD153 + CD4 + T cell─CD30 + fibroblast cellular interaction drives the recruitment and accumulation of immune cells within the salivary glands and supports the formation and maintenance of tertiary lymphoid structure-like tissues that create a pathological microenvironment driving inflammation.
The recognition of this fundamental cellular interaction as a key step in autoimmune pathology has immense potential as a target for therapeutic intervention. The expanded numbers of disease-causing CD153 + CD4 + T cells and CD30 + fibroblasts in tissues may serve as novel biomarkers for diagnosis and/or monitoring of disease progression. Such approaches may help prevent tissue destruction and decelerate disease progression. The therapeutic implication is further supported by the finding that removal of CD153 on CD4 + T cells or neutralization of fibroblast-derived chemokines reduces infiltration of immune cells and significantly halts autoimmune-like pathology in the mouse model.
The key finding of this study is that patients with pSjD also exhibit a similar increase in CD153 + CD4 + T cells and CD30 + fibroblasts that engage in preferential interactions with each other. Such positive correlation of the CD153-CD30 axis with disease severity in human patients significantly enhances its therapeutic potential.
“Our study provides a new perspective on autoimmune diseases and demonstrates that chronic inflammation is maintained not only by abnormal immune cells but also through interactions between immune cells and tissue-resident fibroblasts ,” elaborates Dr. Otsuka. “ Importantly, it highlights that fibroblasts create a pathological microenvironment that worsens the diseased condition through direct interaction with abnormal immune cells. This concept has significant implications in therapeutics for rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, and chronic inflammatory disorders associated with fibrosis,” concludes Dr. Otsuka.
Overall, the study describes a pathogenic, therapeutically targetable CD153 + CD4 + T cell–CD30 + fibroblast axis that perpetuates chronic inflammation in Sjögren disease. The identification of this novel immune-fibroblast crosstalk paves the way for further research in the management of autoimmune diseases.
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Reference
DOI: 10.1038/s41467-026-72975-8
About Tokushima University
Tokushima University established in 1949 is a leading national university in city of Tokushima, Japan. It is organized into six graduate schools and undergraduate faculties. It has been working to further strengthen its education, research and social contributions, in order to make greater advancements that solve global issues while aligning with the UN Sustainable Development Goals (SDGs) from a regional standpoint. The university collaborates with other educational institutes and industries to foster an environment that nurtures future academicians, researchers, and entrepreneurs who have the potential to make the world a better place.
Website: https://www.tokushima-u.ac.jp/english/
About Professor Koji Yasutomo from Tokushima University, Japan
Dr. Koji Yasutomo is a Professor at the Department of Immunology and Parasitology, Graduate School of Medicine, as well as a Distinguished Professor and Chief Research Officer at the Institute of Photonics and Human Health Frontier, Tokushima University, Japan. His research interests include immunology, T cell biology, and genetic analysis of human autoimmune diseases. He has authored over 150 publications in reputed international journals and received numerous awards for his contributions to immunology and autoimmune diseases.
About Dr. Kunihiro Otsuka from Monash University, Australia
Dr. Kunihiro Otsuka is a postdoctoral fellow at Monash University, Australia, having previously served as an Assistant Professor at the Department of Oral and Maxillofacial Surgery, Tokushima University Hospital, Japan. Dr. Otsuka specializes in autoimmune diseases and immunopathology. He received his doctorate in 2019 and has authored around 37 research publications with over 500 citations.
Funding information
This work was supported by JSPS J-PEAKS (JPJS00420240022), JSPS KAKENHI Grant Numbers 20K18479, 23K15976, and 23H00438, Takeda Science Foundation, and the Research Support Project for Life Science and Drug Discovery (BINDS) from AMED (JP22ama121047).
Nature Communications
Experimental study
Animals
A CD4+ T cell-fibroblast crosstalk exacerbates autoimmunity in a mouse model of primary Sjögren disease
12-May-2026
The authors declare no competing interests.