UTX coordinates TCF1 and STAT3 to control progenitor CD8 + T cell fate in autoimmune diabetes

Le résumé fourni par la source

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.

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