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

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 (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.

Growth differentiation factor 15 protects against the aging‐mediated systemic inflammatory response in humans and mice

“…In contrast, the depletion of these inflammatory immune cells ameliorates systemic inflammation and insulin resistance (Jung et al, 2018; Yang et al, 2010). Moreover, T‐cell aging is involved in glucose intolerance and insulin resistance in humans and mice (Yi et al, 2019). In this study, we demonstrated that Gdf15 deficiency enhanced the infiltration of effector T cells and inflammatory macrophages into the liver and adipose tissues, accentuating liver injury, and insulin resistance in aged mice.…”

“…Aging is a major risk factor for various chronic diseases, including type 2 diabetes, neurodegenerative diseases, and malignancies, which are closely related to systemic subclinical inflammation in the absence of overt infections in the elderly (Ortega Martinez de Victoria et al, 2009; Meda et al, 1995; Multhoff, Molls, & Radons, 2011; Yi et al, 2019). Such systemic inflammatory responses are also termed “metaflammation” or “inflammaging” in humans (Franceschi et al, 2007; Hotamisligil, 2017; Sanada et al, 2018).…”

Immunesenescence: A Predisposing Risk Factor for the Development of COVID-19?

“…Owing to impaired metabolism, shortened telomeres and aberrant intracellular signaling ( 33 , 164 , 165 ), reduced proliferation, cytokine production, cytotoxicity and migration are examples of some of the functional impairments that have been reported for T cells isolated from older adults and those with inflammatory co-morbidities ( 33 , 166 , 167 ). The peripheral T cell pools of these adults are enriched with functionally exhausted (TIGIT + , PD-1 + ), highly activated (TIGIT + HLA-DR + CD38 + ), senescent (CD28 − 57 + , CCR7 − 45RA + ) and terminally differentiated (CD27 − 28 − ) CD4 + or CD8 + T cells ( 33 , 168 – 170 ). The most profound changes are witnessed within the CD8 + T cell subset, with the accumulation of CD8 + 28 − T cells of particular significance ( 171 ).…”

The COVID-19 Pandemic: Does Our Early Life Environment, Life Trajectory and Socioeconomic Status Determine Disease Susceptibility and Severity?

“…The mechanistic link between ELA and T2D is re-enforced by the immune disturbances reported. Patients with T2D have a larger number senescent CD8+ cytotoxic T cells and higher levels of systemic inflammation [109,110] that may explain the higher incidence of viral and bacterial infections in diabetic patients [111].…”