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

DCAF1 regulates Treg senescence via the ROS axis during immunological aging

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 8

ROS is important for Treg aging and functional deterioration.

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ROS is important for Treg aging and functional deterioration. (A and B) ...
(A and B) Flow cytometry of ROS levels in aged Tregs (A) and Dcaf1-deficient (CD4-Cre Dcaf1fl/fl) Tregs (B) in the absence (–) or presence (+) of NAC (20 mM) or GSH (10 mM) (blank, no DCFDA; n = 3 mice of 3 experiments; representative results are shown; means ± SD, ****P < 0.0001, by 1-way ANOVA followed by Tukey’s multiple-comparisons test). (C) Proliferation assayed by BrdU incorporation in aged Tregs in the absence (–) or presence (+) of NAC (20 mM) or GSH (10 mM) (n = 4 mice of 4 experiments; representative results are shown; means ± SD, ****P < 0.0001, by 1-way ANOVA followed by Tukey’s multiple-comparisons test). (D) Proliferation assayed by BrdU incorporation in Dcaf1-deficient (CD4-Cre Dcaf1fl/fl) Tregs in the absence (–) or presence (+) of NAC (20 mM) or GSH (10 mM) (n = 4 mice of 4 experiments; representative results are shown; means ± SD, ****P < 0.0001, by 1-way ANOVA followed by Tukey’s multiple-comparisons test). (E) Suppressive activity of aged Tregs without (–) or with (+) pretreatment of NAC (20 mM) or GSH (10 mM), assessed by in vitro suppression assay (n = 3 mice of 3 experiments; representative results are shown; means ± SD, ****P < 0.0001, by 1-way ANOVA followed by Tukey’s multiple-comparisons test). (F) Suppressive activity of Dcaf1-deficient (CD4-Cre Dcaf1fl/fl) Tregs without (–) or with (+) pretreatment of NAC (20 mM) or GSH (10 mM), assessed by in vitro suppression assays (n = 3 mice of 3 experiments; representative results are shown; means ± SD, ***P < 0.001, by 1-way ANOVA followed by Tukey’s multiple-comparisons test).