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 4

DCAF1 is required to prevent Treg aging and inflammaging.

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DCAF1 is required to prevent Treg aging and inflammaging. (A and B) Dist...
(A and B) Distribution of naive and effector memory CD4+ T cells (A) and IFN-γ and IL-4 production of CD4+ T cells (B) in peripheral lymph nodes (PLN) and spleens of 2-month-old mice of indicated genotypes, assessed by flow cytometry (n = 5 mice, 5 experiments; representative results shown; means ± SD, *P < 0.05, **P < 0.01, Mann-Whitney U test). (C and D) Distribution of naive and effector memory CD8+ T cells (C) and IFN-γ and IL-4 production of CD8+ T cells (D) in peripheral lymph nodes and spleens of 2-month-old mice of indicated genotypes, assessed by flow cytometry (n = 5 mice, 5 experiments; representative results shown; means ± SD, **P < 0.01, Mann-Whitney U test). (E) Splenomegaly (left) and increased splenocyte counts (right) in 7- to 12-month-old FGC Dcaf1fl/fl mice (n = 8 mice, 8 experiments; representative results shown, means ± SD, *P < 0.05, 2-sided t test). (F) Histology to compare lymphocytic infiltration in the submandibular gland, kidney, and colon in 7- to 12-month-old littermates of indicated genotypes (scale bar: 100 μm; arrows indicate lymphocyte infiltration foci; results are representative of 5 mice). (G) Comparison of the suppressive activity of Tregs of indicated genotype by in vitro suppression assays (top); the composition of Foxp3+ Tregs was also assessed by flow cytometry (bottom) (n = 3 mice, 3 experiments; representative results shown; means ± SD, **P < 0.01, ***P < 0.001, ****P < 0.0001, 2-way ANOVA followed by Holm-Šidák multiple-comparisons test). (H) Comparison of aging signature gene expression in Tregs and Tconv cells from mice of indicated genotypes, assessed by qRT-PCR analysis of indicated genes (n = 6 mice, 6 experiments; means ± SD, *P < 0.05, **P < 0.01, ****P < 0.0001, 1-way ANOVA followed by Tukey’s multiple-comparisons test).