Immune cell–fibroblast crosstalk may be the key trigger of autoimmune diseases
· Medical Xpressedited by Sadie Harley, reviewed by Robert Egan
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In autoimmune disorders, immune cells targeting "self" proteins are mistakenly activated, resulting in abnormal expansion and responsiveness. These disorders are known to reduce patients' quality of life over a prolonged period. This can be attributed to CD4+ T cells, which 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 nonimmune cell partners.
Fibroblasts emerge as active players
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, revealed that, in addition to the overzealous CD4+ T cells, nonimmune 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.
"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 nonimmune tissue-resident cells are poorly understood," Yasutomo explained.
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.
A damaging cellular partnership
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 slow disease progression.
Evidence points to treatment potential
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. This 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," Otsuka elaborated.
"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," Otsuka concluded.
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.
Publication details
Kunihiro Otsuka et al, A CD4+ T cell-fibroblast crosstalk exacerbates autoimmunity in a mouse model of primary Sjögren disease, Nature Communications (2026). DOI: 10.1038/s41467-026-72975-8
Journal information: Nature Communications
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Allergy and immunologyRheumatology Provided by Tokushima University Who's behind this story?
Sadie Harley
BSc Life Sciences & Ecology. Microbiology lab background with pharmaceutical news experience in oil, gas, and renewable industries. Full profile →
Robert Egan
Bachelor's in mathematical biology, Master's in creative writing. Well-traveled with unique perspectives on science and language. Full profile →
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