UTX coordinates TCF1 and STAT3 to control progenitor CD8+ T cell fate in autoimmune diabetes
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 C. Capati, Dennis J. Chia, Steven D. Mittelman, Christina M. Reh, Jason K. Whitmire, Melissa G. Lechner, Willy Hugo, Maureen A. Su
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 C. Capati, Dennis J. Chia, Steven D. Mittelman, Christina M. Reh, Jason K. Whitmire, Melissa G. Lechner, Willy Hugo, Maureen A. Su
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Research Article Autoimmunity Immunology

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

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.

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 C. Capati, Dennis J. Chia, Steven D. Mittelman, Christina M. Reh, Jason K. Whitmire, Melissa G. Lechner, Willy Hugo, Maureen A. Su

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Figure 6

UTX regulates human stem cell memory CD8+ T cell differentiation into the terminally effector state and interacts with TCF1 and STAT3.

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UTX regulates human stem cell memory CD8+ T cell differentiation into th...
(A) Representative flow cytometric plot of CD8+ T cells from patients with T1D after CRISPR-Cas9 editing with NTC (non-targeting control) sgRNA or UTX-targeting sgRNA. (B) Representative flow cytometric plots (left) and average frequency (right) of TSCM and TTE cells among CD8+CD95+ peripheral blood cells from patients with T1D. Cells were edited with either NTC sgRNA or UTX-targeting sgRNA. (C) In vitro binding assay to show the interaction of UTX-TCF1 (left) and UTX-STAT3 (right) in HEK-293T cells by cotransfection and coimmunoprecipitation. (D) Representative flow cytometric histogram plot of TCF1 expression in CD8+ T cells treated with DMSO or 5 μM TWS119 supplemented with IL-7 (10 ng/mL) and IL-21 (25 ng/mL) for 7 days. (E) Frequencies of TSCM and TTE cells within CD8+CD95+ T cells treated with DMSO or 5 μM of TWS119 for 3 days. Each dot represents a biological replicate (n = 7). **P < 0.01; paired Student’s t test. (F) Representative flow cytometric histogram plot of CD8+ T cells from patients with T1D after CRISPR/Cas9 editing with nontargeting control (NTC) sgRNA or STAT3-targeting sgRNA. (G) Frequencies of TSCM and TTE cells within CD8+CD95+ T cells after CRISPR/Cas9 editing with sgSTAT3 versus a NTC. Left: TSCM; right: TTE. Each dot represents a biological replicate (n = 3). **P < 0.01; paired Student’s t test. (H) Model of how UTX forms a complex with TCF1 and STAT3 to modulate the progenitor and effector programs in promoting T1D development.