Glucose Metabolism Reprogramming of Regulatory T Cells in Concanavalin A-Induced Hepatitis

Abstract

Autoimmune hepatitis (AIH) is an inflammatory liver disease caused by a dysregulated immune response. Although the pathogenesis of AIH remains unclear, impaired regulatory T cells (Tregs) have been considered a driver of AIH development. Unlike autoreactive T cells, Tregs mainly utilize oxidative phosphorylation (OXPHOS) as their energy supply. Elevated glycolysis has been reported to limit the suppressive functions of Tregs. However, whether glucose metabolism reprogramming in Tregs is involved in AIH etiology remains unknown. The aim of this study was to examine alternations in Treg numbers and functions in AIH patients and concanavalin A (Con A)-induced hepatitis, while exploring associations between impaired Tregs and glucose metabolism. The frequency of Tregs was decreased in the peripheral blood but increased in liver biopsies of AIH patients. Moreover, immunosuppressive therapy rescued circulating Tregs in AIH. In Con A-induced immune hepatitis, enhanced intrahepatic Treg accumulation was observed over time, accompanied by reduced splenic Treg numbers. To investigate whether functional impairment of Tregs occurs in AIH, Tregs were isolated from experimental AIH (EAH) model mice and normal controls and the former displayed downregulated mRNA levels of FOXP3, CTLA4, CD103, TIGIT, CD39, and CD73. EAH model-derived Tregs also produced fewer anti-inflammatory mediators (TGF-β and IL-35) than control Tregs. Moreover, enhanced glycolysis and reduced OXPHOS were found in Tregs from EAH model mice, as reflected by elevated levels of key glycolytic enzymes (HK2, PK-M2, and LDH-A) and a decreased ATP concentration. This study revealed a decreased peripheral Treg frequency and abnormal intrahepatic Treg infiltration in AIH. It is first reported that glucose metabolism reprogramming is associated with decreases and functional impairments in the Treg population, promoting AIH development. Targeting glucose metabolism may provide novel insights for the treatment of AIH.

The role of metabolism on regulatory T cell development and its impact in tumor and transplantation immunity

“…Depending on the immunosuppressive function of Treg cells, metabolism can be reprogrammed between glycolysis ( 60 ) and OXPHOS ( 61 ). HIF-1α can participate in regulation cytokine expression Treg.…”

Blockade of PGK1 and ALDOA enhances bilirubin control of Th17 cells in Crohn’s disease

“…It is plausible postulating that a high glycolysis rate might be the consequence of defective AhR control over metabolism, resulting from a hypoxic inflammatory environment and leading to high PGK1/ALDOA and decreased CD39 expression. Links between CD39 and purinergic mediators with metabolism have been reported before in the context of hepatocellular carcinoma, where Cd39 deficiency was associated with increased production of lactate 38 ; and in liver inflammation, where low CD39 and CD73 levels were noted in combination with upregulated hexokinase 2, pyruvate kinase M2 (PKM2) and lactate dehydrogenase 39 . Additional links were reported in the context of Treg adoptive transfer, where expanded Tregs were found to switch to aerobic glycolysis while enhancing their suppressor properties as a result of HIF-1α induced expression of CD73 40 .…”

CD73, a significant protein in liver diseases

“…CD73 around the surface of normal Treg cells mediates the production of immune-suppressing adenosine ( 24 ), blocks cell communication, inhibits overimmunity, and simultaneously upregates CD73 expression ( 10 ). However, the level of CD73 on the damaged Treg surface was down-regulated ( 37 ), the secretion of TGF-β and other anti-inflammatory factors was reduced ( 38 ), and the immunosuppressive function of Treg was defective ( 39 ), leading to the occurrence of AIH. On the other hand, IL-6 and TGF-β can induce the expression of CD39 and CD73 in helper T17 cells (Th17), stimulate the production of adenosine, inhibit the transformation of naive T cells into Th ( 40 ), along with reducing the production of pro-inflammatory cytokines ( 41 ), which can be charactered as immune deficiency.…”