T-cell senescence contributes to abnormal glucose homeostasis in humans and mice
- Yi, Hyon-Seung; Kim, So Yeon; Kim, Jung Tae; Lee, Young-Sun; Moon, Ji Sun; Kim, Mingyo; Kang, Yea Eun; Joung, Kyong Hye; Lee, Ju Hee; Kim, Hyun Jin; Chun, Kwangsik; Shong, Minho; Ku, Bon Jeong
- Issue Date
- Nature Publishing Group
- Cell Death and Disease, v.10
- Journal Title
- Cell Death and Disease
- 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 (CD28(-)CD57(+)) 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.
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- 2. Clinical Science > Department of Gastroenterology and Hepatology > 1. Journal Articles
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