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.
Bibliographical noteFunding Information:
This study was supported by the Korean Health Technology R&D Project (HI15C1754) through the Korean Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare and the Basic Science Research Program (2018R1A2A1A05076997 to S-.J.H.) through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning.
© 2019. The Korean Association of Immunologists.
All Science Journal Classification (ASJC) codes
- Immunology and Allergy
- Infectious Diseases