Unveiling the identity of Crohn's disease T cells

Osaka, Japan - The research group led by Drs. Mitsuru Arase, Mari Murakami, and Prof. Kiyoshi Takeda (Graduate School of Medicine/ Immunology Frontier Research Center at The University of Osaka) revealed that transcription factors RUNX2 and BHLHE40 play crucial roles in inducing T cells involved in Crohn's disease.

Crohn's disease is an intractable disorder characterized by chronic inflammation in the digestive tract. Tissue-resident memory T cells (T_RM), which persist in long-term in the intestinal mucosa, have been implicated in disease pathogenesis, but it has not been clear how these cells are induced.

In this study, though comprehensive single-cell analysis of gut T cells from Crohn's disease patients, the research group identified the accumulation of T_RM with high expression of transcription factors RUNX2 and BHLHE40. RUNX2 is known as a master regulator of osteoblast differentiation and maturation; however, a different RUNX2 variant was expressed in Crohn's disease T_RM, distinct from that found in bone.

Overexpression of RUNX2 and BHLHE40 in blood-derived T cells from healthy individuals enhanced the production of inflammatory cytokine IFN-γ and cytotoxic molecule granzyme B (GZMB), and promoted tissue-retentive properties. Conversely, repression of these factors in patient-derived gut T cells reduced their inflammatory and tissue-retaining characteristics.

These findings indicate that RUNX2 and BHLHE40 drive pathogenic T_RM differentiation and may represent novel therapeutic targets for chronic inflammation and relapse in Crohn’s disease.

"In this research, we successfully identified a factor that induces T cells involved in the symptoms of Crohn's disease. We sincerely hope that the results of this study will contribute to the development of new diagnostic methods and therapeutic strategies for Crohn's disease. We extend our deepest gratitude to all collaborators and to the patients who generously provided samples for this study." says Dr. Mari Murakami, the lead author of the study.

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The article, “Multi-omics uncovers transcriptional programs of gut-resident memory CD4⁺ T cells in Crohn's Disease,” will be published in Journal of Experimental Medicine at DOI: https://doi.org/ 10.1084/jem.20242106.

About The University of Osaka

The University of Osaka was founded in 1931 as one of the seven imperial universities of Japan and is now one of Japan's leading comprehensive universities with a broad disciplinary spectrum. This strength is coupled with a singular drive for innovation that extends throughout the scientific process, from fundamental research to the creation of applied technology with positive economic impacts. Its commitment to innovation has been recognized in Japan and around the world. Now, The University of Osaka is leveraging its role as a Designated National University Corporation selected by the Ministry of Education, Culture, Sports, Science and Technology to contribute to innovation for human welfare, sustainable development of society, and social transformation.

Website: https://resou.osaka-u.ac.jp/en