DCAF1 regulates Treg senescence via the ROS axis during immunological aging

J Clin Invest. 2020 Nov 2;130(11):5893-5908. doi: 10.1172/JCI136466.

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.

Keywords: Aging; Cellular senescence; Immunology; Inflammatory bowel disease; T cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / genetics
  • Aging / immunology*
  • Aging / pathology
  • Animals
  • Cellular Senescence / genetics
  • Cellular Senescence / immunology*
  • Disease Models, Animal
  • Down-Regulation / genetics
  • Down-Regulation / immunology
  • Glutathione S-Transferase pi / genetics
  • Glutathione S-Transferase pi / immunology
  • Inflammatory Bowel Diseases / genetics
  • Inflammatory Bowel Diseases / immunology
  • Inflammatory Bowel Diseases / pathology
  • Mice
  • Mice, Knockout
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / immunology*
  • Reactive Oxygen Species / immunology*
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / pathology

Substances

  • Reactive Oxygen Species
  • Glutathione S-Transferase pi
  • Gstp1 protein, mouse
  • Protein Serine-Threonine Kinases
  • VprBP protein, mouse