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DCAF1 regulates Treg senescence via the ROS axis during immunological aging
Zengli Guo, … , Jenny P.-Y. Ting, Yisong Y. Wan
Zengli Guo, … , Jenny P.-Y. Ting, Yisong Y. Wan
Published July 30, 2020
Citation Information: J Clin Invest. 2020;130(11):5893-5908. https://doi.org/10.1172/JCI136466.
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Research Article Aging Immunology Article has an altmetric score of 8

DCAF1 regulates Treg senescence via the ROS axis during immunological aging

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Abstract

As a hallmark of immunological aging, low-grade, chronic inflammation with accumulation of effector memory T cells contributes to increased susceptibility to many aging-related diseases. While the proinflammatory state of aged T cells indicates a dysregulation of immune homeostasis, whether and how aging drives regulatory T cell (Treg) aging and alters Treg function are not fully understood owing to a lack of specific aging markers. Here, by a combination of cellular, molecular, and bioinformatic approaches, we discovered that Tregs senesce more severely than conventional T (Tconv) cells during aging. We found that Tregs from aged mice were less efficient than young Tregs in suppressing Tconv cell function in an inflammatory bowel disease model and in preventing Tconv cell aging in an irradiation-induced aging model. Furthermore, we revealed that DDB1- and CUL4-associated factor 1 (DCAF1) was downregulated in aged Tregs and was critical to restrain Treg aging via reactive oxygen species (ROS) regulated by glutathione-S-transferase P (GSTP1). Importantly, interfering with GSTP1 and ROS pathways reinvigorated the proliferation and function of aged Tregs. Therefore, our studies uncover an important role of the DCAF1/GSTP1/ROS axis in Treg senescence, which leads to uncontrolled inflammation and immunological aging.

Authors

Zengli Guo, Gang Wang, Bing Wu, Wei-Chun Chou, Liang Cheng, Chenlin Zhou, Jitong Lou, Di Wu, Lishan Su, Junnian Zheng, Jenny P.-Y. Ting, Yisong Y. Wan

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Figure 6

DCAF1 is required to prevent human T cell aging.

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DCAF1 is required to prevent human T cell aging.
(A) The protein express...
(A) The protein expression of DCAF1 and β-actin in human 293T cells transduced with lentivirus expressing 2 shRNAs targeting Dcaf1 and scrambled control for 4 days. The results are representative of 3 independent experiments. (B) Flow cytometry of ROS level in human T cells transduced with lentivirus expressing 2 shRNAs targeting Dcaf1 and scrambled control for 4 days, analyzed by 2′,7′-dichlorofluorescin diacetate (DCFDA) (gray area, no DCFDA; n = 4; representative results of 2 independent experiments are shown; means ± SD, **P < 0.01, by 1-way ANOVA followed by Tukey’s multiple-comparisons test). (C) SA-β-gal activity in human T cells transduced with lentivirus expressing 2 shRNAs targeting Dcaf1 and scrambled control for 6 days, assessed by flow cytometry with the fluorescent β-gal substrate C12FDG (gray area, no C12FDG; n = 4; representative flow cytometry results are shown; means ± SD, **P < 0.01, ***P < 0.001, by 1-way ANOVA followed by Tukey’s multiple-comparisons test). (D) qRT-PCR analysis to determine mRNA expression of p16Ink4a in human T cells transduced with 2 shRNAs targeting Dcaf1 and scrambled control for 6 days (n = 6 from 2 independent experiments; means ± SD, **P < 0.01, ****P < 0.0001, by 1-way ANOVA followed by Tukey’s multiple-comparisons test).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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