Targeting key transcription factors may offer new Crohn’s disease therapy

A research group has 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 (TRM), which persist 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, through comprehensive single-cell analysis of gut T cells from Crohn’s disease patients, the research group identified the accumulation of TRM 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 TRM, 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 TRM differentiation and may represent novel therapeutic targets for chronic inflammation and relapse in Crohn’s disease. The work is published in the journal Journal of Experimental Medicine. The study was led by Drs. Mitsuru Arase, Mari Murakami, and Prof. Kiyoshi Takeda (Graduate School of Medicine/ Immunology Frontier Research Center at The University of Osaka).

“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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