Macroautophagy regulates T helper cell activation and tolerance

Abstract

Abstract Macroautophagy is a catabolic process whereby cell components, which range from soluble proteins to whole organelles, are sequestered in de novo formed double-membrane autophagosomes that fuse with lysosomes to degrade their cargo. Effector T helper cells induce macroautophagy during activation to maintain cell proliferation and cytokine production. T cells that are unable to upregulate macroautophagy activity show a reduction in ATP generation, suggesting that macroautophagy is necessary to maintain the energy metabolism required to meet the demands of T cell activation. It is presently unknown whether macroautophagy regulates the activation state and functional capacity of CD4+T cells. We explored the instructive role of macroautophagy in effector T helper cell activation and tolerance. Inhibition of macroautophagy during activation of CD4+T helper type 1 (TH1) cells induces a long-lasting state of hyporesponsiveness, with a molecular signature that resembles that of anergic T cells. Moreover, inhibition of macroautophagy prevented activated TH1 cells from upregulating glycolysis and mitochondrial respiration, supporting that macroautophagy may regulate metabolic homeostasis during activation of effector T helper cells. Consequently, inhibition of macroautophagy in vivo prevents CD4+ T cell activation in response to immunization and results in decreased severity of experimental autoimmune encephalomyelitis. Our data support that macroautophagy, likely by regulating metabolism, is necessary for the activation of effector T helper cells and that its absence induces a tolerant state.