UTX coordinates TCF1 and STAT3 to control progenitor CD8+ T cell fate in autoimmune diabetes
Name
196325.2-20260213181642-covered-4fa089109ce452e764bbb8648b44a723.pdf
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Published version
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2.09 MB
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Author(s)
Chen, Ho-Chung
Bang, Madison F
Wang, Hsing-Hui
Shpargel, Karl B
Kohn, Lisa A
Sailer, David
Zhang, Shile
McCarthy, Ethan C
Seyedsadr, Maryamsadat
Stevens, Satchel
Date Issued
December 16, 2025
Journal
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Version
Final published version
Abstract
Type 1 diabetes mellitus (T1D) is a chronic disease caused by an unremitting autoimmune attack on pancreatic β cells. This
autoimmune chronicity is mediated by stem-like progenitor CD8+
T cells that continually repopulate the pool of β cell–specific
cytolytic effectors. Factors governing the conversion of progenitors to effectors, however, remain unclear. T1D has been
linked to a chromosomal region (Xp13-p11) that contains the epigenetic regulator UTX, which suggests a key role for UTX in
T1D pathogenesis. Here, we show that T cell–specific UTX deletion in NOD mice protects against T1D development. In T cells
of NOD mice and patients with T1D, UTX ablation resulted in the accumulation of CD8+
progenitor cells with a concomitant
decrease of effector cells, suggesting a key role for UTX in poising progenitors for transition to effectors. Mechanistically,
UTX’s role in T1D was independent of its inherent histone demethylase activity but instead relied on binding with
transcription factors (TCF1 and STAT3) to coregulate genes important in the maintenance and differentiation of progenitor
CD8+
T cells. Together, these findings identify a critical role for UTX in T1D and the UTX:TCF1:STAT3 complex as a therapeutic
target for terminating the long-lived autoimmune response.
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DOI of Published Version
https://doi.org/10.1172/jci196325
