Researchers uncover key mechanism driving chronic Sjögren disease

Sjögren disease, an autoimmune disease characterized by dry mouth and dry eyes, may reduce patients’ quality of life. While CD4+ T cells are key drivers of immune-mediated tissue damage and chronic inflammation, the role of pathogenic CD4+ T cell subsets and their non-immune cell partners remains unexplored. Researchers have now identified the preferential CD4+ T cell-fibroblast cellular interaction that amplifies inflammatory proteins and tissue damage, representing a potential target for therapeutic intervention in Sjögren disease.

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.

Source:

Tokushima University

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