T-cell senescence contributes to abnormal glucose homeostasis in humans and mice

Hyon Seung Yi, So Yeon Kim, Jung Tae Kim, Young Sun Lee, Ji Sun Moon, Mingyo Kim, Yea Eun Kang, Kyong Hye Joung, Ju Hee Lee, Hyun Jin Kim, Kwangsik Chun, Minho Shong, Bon Jeong Ku

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6 Citations (Scopus)

Abstract

Chronic inflammation is a driving force for the development of metabolic disease including diabetes and obesity. However, the functional characteristics of T-cell senescence in the abnormal glucose homeostasis are not fully understood. We studied the patients visiting a hospital for routine health check-ups, who were divided into two groups: normal controls and people with prediabetes. Gene expression profiling of peripheral blood mononuclear cells from normal controls and patients with type 2 diabetes was undertaken using microarray analysis. We also investigated the immunometabolic characteristics of peripheral and hepatic senescent T cells in the normal subjects and patients with prediabetes. Moreover, murine senescent T cells were tested functionally in the liver of normal or mice with metabolic deterioration caused by diet-induced obesity. Human senescent (CD28CD57+) CD8+ T cells are increased in the development of diabetes and proinflammatory cytokines and cytotoxic molecules are highly expressed in senescent T cells from patients with prediabetes. Moreover, we demonstrate that patients with prediabetes have higher concentrations of reactive oxygen species (ROS) in their senescent CD8+ T cells via enhancing capacity to use glycolysis. These functional properties of senescent CD8+ T cells contribute to the impairment of hepatic insulin sensitivity in humans. Furthermore, we found an increase of hepatic senescent T cells in mouse models of aging and diet-induced obesity. Adoptive transfer of senescent CD8+ T cells also led to a significant deterioration in systemic abnormal glucose homeostasis, which is improved by ROS scavengers in mice. This study defines a new clinically relevant concept of T-cell senescence-mediated inflammatory responses in the pathophysiology of abnormal glucose homeostasis. We also found that T-cell senescence is associated with systemic inflammation and alters hepatic glucose homeostasis. The rational modulation of T-cell senescence would be a promising avenue for the treatment or prevention of diabetes.

Original languageEnglish
Article number249
JournalCell Death and Disease
Volume10
Issue number3
DOIs
Publication statusPublished - 2019 Mar 1

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

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  • Cite this

    Yi, H. S., Kim, S. Y., Kim, J. T., Lee, Y. S., Moon, J. S., Kim, M., Kang, Y. E., Joung, K. H., Lee, J. H., Kim, H. J., Chun, K., Shong, M., & Ku, B. J. (2019). T-cell senescence contributes to abnormal glucose homeostasis in humans and mice. Cell Death and Disease, 10(3), [249]. https://doi.org/10.1038/s41419-019-1494-4