A research group including Professor Koji Yasutomo of the Department of Immunology and Parasitology, Graduate School of Biomedical Sciences, Tokushima University, and Assistant Professor Kunihiro Otsuka of the Department of Oral Surgery, Tokushima University Hospital (at the time of the research), has uncovered a novel mechanism that amplifies inflammation in Sjögren's disease, an autoimmune disorder. The team detailed how interactions between tissue-resident fibroblasts and CD4-positive (CD4+) T cells expressing CD153, a molecule responsible for intercellular communication, drive the disease forward. This interaction promotes immune cell aggregation by inducing fibroblast proliferation and chemokine production, resulting in sustained amplification of inflammation. These findings are highly anticipated to lead to the development of new therapeutic strategies. The study was published in the May 12 issue of Nature Communications.
Pathological progression is promoted in the order of (1) to (4). (1) CD4+ T cells infiltrating the salivary gland induce CD30 expression on fibroblasts. Subsequently, (2) CD153 expressed on CD4+ T cells interacts with CD30 on fibroblasts, promoting (3) fibroblast proliferation and (4) production of various chemokines. At the same time, CD153+ T cells are presumed to recognize self-antigens, leading to their proliferation.
Provided by Professor Koji Yasutomo, Tokushima University
Autoimmune diseases occur when the immune system, which is fundamentally designed to protect the body from external threats, mistakenly attacks its own tissues, resulting in intractable, chronic inflammation. Among these conditions, Sjögren's disease is characterized by the infiltration of lymphocytes into exocrine glands, such as the lacrimal (tear) and salivary glands, leading to core symptoms like dry eyes and dry mouth.
Historically, abnormalities in immune cells, particularly CD4+ T cells, have been viewed as the primary drivers of the onset and progression of autoimmune diseases. In recent years, however, scientists have pointed out that non-immune cells like fibroblasts are not merely passive structural scaffolds, but active regulators of the immune response. Specifically, it had been suggested that fibroblasts within tertiary lymphoid structures, which are organized aggregates of immune cells that form at sites of chronic inflammation, might play a role in gathering immune cells, although the details remained unclear.
To investigate this, the research group focused on the cellular crosstalk between immune cells and tissue cells that accelerates autoimmune diseases. Utilizing a Sjögren's disease mouse model and human patient samples, they integrated single-cell RNA sequencing (scRNA-seq) with histological analysis to meticulously evaluate the intercellular interactions at the site of the lesions.
Their analysis revealed that a specific population of CD4+ T cells expressing CD153 increases from the early stages of the disease and is actively involved in driving the progression of inflammation. Furthermore, the researchers discovered that these CD153+ CD4+ T cells interact directly with CD30, a receptor expressed on the fibroblasts within the tissue.
This direct interaction activates the fibroblasts, triggering them to proliferate and begin producing chemokines. Fibroblasts are widely distributed throughout skin and internal organs, where they maintain and repair tissue structures by producing extracellular matrix components like collagen. Chemokines are a type of cytokine that controls the migration activity of white blood cells and lymphocytes. Furthermore, these chemokines induce the accumulation of T cells and B cells, promoting further accumulation of immune cells at the inflammatory site and the formation of tertiary lymphoid tissues. This mechanism was also observed inside human tissue biopsy sections.
To verify the mechanism, blocking the CD153-CD30 pathway suppressed fibroblast proliferation and chemokine production. It was also confirmed that infiltration of inflammatory cells and tissue damage were significantly reduced.
Yasutomo stated: "Regarding the onset and progression mechanism of autoimmune diseases, it has not been sufficiently clarified how CD4+ T cells and fibroblasts constituting tissues directly interact to sustain and amplify inflammation. In this study targeting Sjögren's disease, we clarified the mechanism by which CD4+ T cells expressing CD153 activate fibroblasts expressing CD30. In the future, we expect that targeting this T cell-fibroblast interaction mediated by CD153-CD30 will lead to the development of new treatments."
Journal Information
Publication: Nature Communications
Title: A CD4+ T cell-fibroblast crosstalk exacerbates autoimmunity in a mouse model of primary Sjögren disease
DOI: 10.1038/s41467-026-72975-8
This article has been translated by JST with permission from The Science News Ltd. (https://sci-news.co.jp/). Unauthorized reproduction of the article and photographs is prohibited.