UTX coordinates TCF1 and STAT3 to control progenitor CD8+ T cell fate in autoimmune diabetes
Year: 2025
Type: article
Abstract: Type 1 Diabetes Mellitus (T1D) is driven by chronic autoimmune destruction of pancreatic beta cells, primarily mediated by CD8+ progenitor T cells that replenish pathogenic effectors. However, the regulatory mechanisms guiding this progenitor-to-effector transition remain unclear. T1D susceptibility has been linked to an X chromosome region (Xp13-p11) containing UTX, an epigenetic regulator. Here, we show that T cell-specific deletion of UTX in NOD mice prevents T1D, implicating UTX as a key driver of disease. UTX-deficient mice exhibit an accumulation of CD8+ progenitors and a reduction in effectors, suggesting that UTX facilitates progenitor differentiation to effectors. This function is independent of UTX's demethylase activity and instead depends on interactions with transcription factors TCF1 and STAT3, which regulate progenitor T cells' maintenance and differentiation. These findings reveal that UTX facilitates T1D pathogenesis by enabling the transition of progenitors into cytolytic effectors. Targeting the UTX: TCF1: STAT3 complex may thus offer a novel strategy to terminate the long-lived autoimmune response in T1D.
DOI: 10.1172/jci196325
Authors: Ho-Chung Chen, Madison F. Bang, Hsing-Hui Wang, Karl B. Shpargel, Lisa A. Kohn, David Sailer, Shile Zhang, Ethan C. McCarthy, Maryamsadat Seyedsadr, Satchel Stevens, Caitlyn L. H. Pham, Zikang Zhou, Xihui Yin, Nicole M. Wilkinson, Esther M. Peluso, Christian Bustillos, Jessica G. Ortega, Lixin Yang, Ashlyn A. Buzzelli, Reina Capati, Dennis J. Chia, Steven D. Mittelman, Christina M. Reh, Jason K. Whitmire, Melissa G. Lechner, Willy Hugo, Maureen A. Su
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,200
Funders: U.S. Department of Defense, National Institutes of Health, University of California, Los Angeles, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Dental and Craniofacial Research, David Geffen School of Medicine, University of California, Los Angeles
Awards: Regulation of CD8+ T cell responses to chronic virus infection, Enhancer activation mechanisms in cranial neural crest osteoblast differentiation, Epigenetic Mechanisms in Type 1 Diabetes, G4631708006, PATHOGENIC T CELLS IN GUILLAIN BARRE SYNDROME, Mechanisms of Thyroid Autoimmunity in Checkpoint Immunotherapy, Sex Differences in NK Cells Mediated by X-linked UTX, Identifying new immunotherapeutic targets for endocrine autoimmunity.
OpenAlex ID: W4417400680