RESUMO
T cell subsets including effector (Teff), regulatory (Treg), and memory (Tmem) cells are characterized by distinct metabolic profiles that influence their differentiation and function. Previous research suggests that engagement of long-chain fatty acid oxidation (LC-FAO) supports Foxp3+ Treg cell and Tmem cell survival. However, evidence for this is mostly based on inhibition of Cpt1a, the rate-limiting enzyme for LC-FAO, with the drug etomoxir. Using genetic models to target Cpt1a specifically in T cells, we dissected the role of LC-FAO in primary, memory, and regulatory T cell responses. Here we show that the ACC2/Cpt1a axis is largely dispensable for Teff, Tmem, or Treg cell formation, and that the effects of etomoxir on T cell differentiation and function are independent of Cpt1a expression. Together our data argue that metabolic pathways other than LC-FAO fuel Tmem or Treg differentiation and suggest alternative mechanisms for the effects of etomoxir that involve mitochondrial respiration.
Assuntos
Acetil-CoA Carboxilase/fisiologia , Linfócitos T CD8-Positivos/metabolismo , Carnitina O-Palmitoiltransferase/fisiologia , Compostos de Epóxi/farmacologia , Ácidos Graxos/metabolismo , Memória Imunológica/efeitos dos fármacos , Mitocôndrias/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Acetil-CoA Carboxilase/genética , Animais , Carnitina O-Palmitoiltransferase/genética , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Criança , Pré-Escolar , Feminino , Técnicas de Inativação de Genes , Humanos , Ativação Linfocitária/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oxirredução/efeitos dos fármacos , Fosforilação Oxidativa/efeitos dos fármacos , Linfócitos T Reguladores/metabolismoRESUMO
The AMP-activated protein kinase (AMPK) is a key metabolic regulator that both senses changes in cellular energy levels and activates pathways to maintain cellular energy balance. AMPK achieves this by stimulating catabolic pathways that generate ATP and inhibiting biological pathways that consume ATP consumption. Recent work has established that AMPK is activated in T cells by both immunological and environmental stimuli, and plays an important role in T cell metabolism, in part by controlling T cell 'metabolic plasticity'. Recent data have revealed distinct functions for AMPK in T cells, including effects on memory T cell development, cytokine production, and potentially anti-tumor responses. In this review, we discuss recent advances in our understanding of AMPK function in T cells, and discuss future research areas for this energy-sensing pathway in lymphocytes.
