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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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 1

Preferential Treg aging in young and aged mice.

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Preferential Treg aging in young and aged mice. (A) Proliferation of CD4...
(A) Proliferation of CD4+Foxp3+ (Treg) and CD4+Foxp3– (Tconv) cells from young and aged (more than 18-month-old) mice 3 days after activation when cultured in the same well, analyzed by CFSE dilution and flow cytometry (n = 7 mice of 3 experiments; representative results are shown; means ± SD, ****P < 0.0001, by 1-way ANOVA followed by Tukey’s multiple-comparisons test). (B) SA-β-gal activity of CD4+CD25+ Tregs and CD4+CD25– Tconv cells in splenocytes from young and aged mice, assessed by flow cytometry with the fluorescent β-gal substrate C12FDG (gray area, no C12FDG; n = 6 mice of 3 experiments; representative flow cytometry results are shown; means ± SD, ****P < 0.0001, by 1-way ANOVA followed by Tukey’s multiple-comparisons test). (C) Elevated aging program in aged Tregs (left panel) and aged Tconv cells (right panel) revealed by GSEA of RNA-Seq data sets. (D and E) Preferential upregulation of senescence signature genes in aged Tregs, revealed by heatmap analysis of RNA-Seq data sets (D) and by quantitative reverse transcriptase PCR (qRT-PCR) analysis of indicated genes (n = 6 mice of 3 experiments; means ± SD, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, by 1-way ANOVA followed by Tukey’s multiple-comparisons test) (E). (F) Preferential upregulation of the aging program in Tregs in both young (left) and aged (right) mice, revealed by GSEA of RNA-Seq data sets.