Metabolic Reprogramming by the Excessive AMPK Activation Exacerbates Antigen-Specific Memory CD8+ T Cell Differentiation after Acute Lymphocytic Choriomeningitis Virus Infection
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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.
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.
참고문헌 (22)
- O'Neill LA, "A guide to immunometabolism for immunologists", Nat Rev Immunol, 16, pp.553~565 (2016)
- Pearce EL, "Fueling immunity: insights into metabolism and lymphocyte function", Science, 342, pp.1242454~ (2013)
- O'Sullivan D, "Targeting T cell metabolism for therapy", Trends Immunol, 36, pp.71~80 (2015)
- Buck MD, "T cell metabolism drives immunity", J Exp Med, 212, pp.1345~1360 (2015)
- Sukumar M, "Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function", J Clin Invest, 123, pp.4479~4488 (2013)
- Araki K, "mTOR regulates memory CD8 T-cell differentiation", Nature, 460, pp.108~112 (2009)
- Pearce EL, "Enhancing CD8 T-cell memory by modulating fatty acid metabolism", Nature, 460, pp.103~107 (2009)
- Rolf J, "AMPKα1: a glucose sensor that controls CD8 T-cell memory", Eur J Immunol, 43, pp.889~896 (2013)
- Phan AT, "Constitutive glycolytic metabolism supports CD8+ T cell effector memory differentiation during viral infection", Immunity, 45, pp.1024~1037 (2016)
- Choi J, "Inhibiting stemness and invasive properties of glioblastoma tumorsphere by combined treatment with temozolomide and a newly designed biguanide (HL156A).", Oncotarget, 7, pp.65643~65659 (2016)
- Lam TG, "New metformin derivative HL156A prevents oral cancer progression by inhibiting the insulin-like growth factor", AKT, Cancer Sci, pp.2018, 109[DOI]
- Ju KD, "HL156A, a novel AMP-activated protein kinase activator, is protective against peritoneal fibrosis in an in vivo and in vitro model of peritoneal fibrosis", Am J Physiol Renal Physiol, 310, pp.F342~F350 (2016)
- Tsogbadrakh B, "HL156A, a novel pharmacological agent with potent adenosine-monophosphate-activated protein kinase (AMPK) activator activity ameliorates renal fibrosis in a rat unilateral ureteral obstruction model", PLoS One, 13, pp.e0201692~ (2018)
- Murali-Krishna K, "Counting antigen-specific CD8 T cells: a reevaluation of bystander activation during viral infection", Immunity, 8, pp.177~187 (1998)
- Kaech SM, "Transcriptional control of effector and memory CD8+ T cell differentiation", Nat Rev Immunol, 12, pp.749~761 (2012)
- Betts MR, "Sensitive and viable identification of antigen-specific CD8+ T cells by a flow cytometric assay for degranulation", J Immunol Methods, 281, pp.65~78 (2003)
- Mittendorf EA, "Evaluation of the CD107 cytotoxicity assay for the detection of cytolytic CD8+ cells recognizing HER2", neu vaccine peptides, 2005, pp.92, 85~93
- Aktas E, "Relationship between CD107a expression and cytotoxic activity", Cell Immunol, 254, pp.149~154 (2009)
- Tian Y, "Cytotoxic CD4 T cells: differentiation, function, and application to dengue virus infection", Front Immunol, 7, pp.531~531 (2016)
- Kim SA, "Antioxidant modifications induced by the new metformin derivative HL156A regulate metabolic reprogramming in SAMP1", kl −, Aging (Albany NY), pp.2018, 10[DOI]
- Lee HS, "AMP-activated protein kinase activator, HL156A reduces thioacetamide-induced liver fibrosis in mice and inhibits the activation of cultured hepatic stellate cells and macrophages", Int J Oncol, 49, pp.1407~1414 (2016)
- Yin Y, "Normalization of CD4+ T cell metabolism reverses lupus", Sci Transl Med, 7(274) (2015)