Immune Netw.  2019 Apr;19(2):e11. 10.4110/in.2019.19.e11.

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

• Son J
• Cho YW
• Woo YJ
• Baek YA
• Kim EJ
• Cho Y
• Kim JY
• Kim BS
• Song JJ
• Ha SJ

• KMID: 2444159
• DOI: http://doi.org/10.4110/in.2019.19.e11

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.

Keyword

Metabolic reprogramming; AMP-activated protein kinases; Immunologic memory; IM156

MeSH Terms

AMP-Activated Protein Kinases*
Cell Differentiation*
Fibrosis
Glycolysis
Immunologic Memory
In Vitro Techniques
Lymphocytic choriomeningitis virus*
Lymphocytic Choriomeningitis*
Memory*
Metformin
Oxidative Phosphorylation
T-Lymphocytes
AMP-Activated Protein Kinases
Metformin