Metabolic Reprogramming by the Excessive AMPK Activation Exacerbates Antigen-Specific Memory CD8⁺T Cell Differentiation after Acute Lymphocytic Choriomeningitis Virus Infection

Abstract

During virus infection, T cells must be adapted to activation and lineage differentiation states via metabolic reprogramming. Whereas effector CD8 + T cells preferentially use glycolysis for their rapid proliferation, memory CD8 + T cells utilize oxidative phosphorylation for their homeostatic maintenance. Particularly, enhanced AMP-activated protein kinase (AMPK) activity promotes the memory T cell response through different pathways. However, the level of AMPK activation required for optimal memory T cell differentiation remains unclear. A new metformin derivative, IM156, formerly known as HL156A, has been reported to ameliorate various types of fibrosis and inhibit in vitro and in vivo tumors by inducing AMPK activation more potently than metformin. Here, we evaluated the in vivo effects of IM156 on antigen-specific CD8 + T cells during their effector and memory differentiation after acute lymphocytic choriomeningitis virus infection. Unexpectedly, our results showed that in vivo treatment of IM156 exacerbated the memory differentiation of virus-specific CD8 + T cells, resulting in an increase in short-lived effector cells but decrease in memory precursor effector cells. Thus, IM156 treatment impaired the function of virus-specific memory CD8 + T cells, indicating that excessive AMPK activation weakens memory T cell differentiation, thereby suppressing recall immune responses. This study suggests that metabolic reprogramming of antigen-specific CD8 + T cells by regulating the AMPK pathway should be carefully performed and managed to improve the efficacy of T cell vaccine.

Analysis of the Whole-Genome Sequences from an Equus Parent-Offspring Trio Provides Insight into the Genomic Incompatibilities in the Hybrid Mule

“…An appropriate cellular energy environment ensures that naive T cells successfully proliferate and differentiate into specific T cell subsets for an effective immune response. Multiple metabolism-related signaling pathways were enriched in this study, such as PI3K-Akt (ecb04151), mTOR (ecb04150), AMPK (ecb04152), and Foxo (ecb04068) pathways, which are required to coordinate T cell metabolic activity [ 50 , 51 , 52 , 53 ].…”

Effects of altered glycolysis levels on CD8+ T cell activation and function

“…However, there are still many gaps in the existing studies, such as the metabolic shift from glycolysis to FAO to support memory CD8 + T cell differentiation [48], and the specific mechanisms underlying this remain unclear. For effector CD8 + T cells, although Fig.…”

“…During viral infection, T cells adapt to the activated and differentiated state via metabolic reprogramming [ 48 ]. Moreover, metabolic alterations induced by external stimuli also have an important impact on CD8 + T cell differentiation, because the bioenergetic metabolism of naive CD8 + T cells shifts from OXPHOS to aerobic glycolysis and further proliferation in response to antigenic stimulation.…”

Creatine in T Cell Antitumor Immunity and Cancer Immunotherapy

“…In order to restore cell energy homeostasis, activated AMPK stimulates ATP-producing catabolic pathways and inhibits ATP-consuming anabolic pathways. While AMPK as a key metabolic regulator plays critical role in T cell metabolism and function [ 50 , 51 , 52 , 53 ], excessive AMPK activation impairs the function of antigen-specific CD8 T cells [ 54 ]. In CrT -KO CD8 T cells, the decreased ATP levels were associated with increased activation of AMPK.…”