Inhibition of activation-induced autophagy induces hyporesponsiveness in effector T helper cells

Abstract

Abstract T cell activation requires the regulation of signaling pathways and metabolic programs downstream of T cell receptor and CD28 engagement. Upon activation, effector CD4+ T helper cells induce autophagy, a lysosomal-mediated protein degradation mechanism. The controlled degradation and recycling of cell components allow effector T helper cells to respond to various types of stimuli. However, it is unknown how autophagy may regulate the antigenic responses and functional capacity of CD4+T cells. We found that inhibiting activation-induced autophagy in CD4+T helper type 1 (TH1) cells induces a hyporesponsive state. This hyporesponsiveness is associated with a reduction in ATP generation and decreased glycolysis and mitochondrial respiration. Moreover, T cells that are unable to upregulate autophagy accumulate a protein tyrosine phosphatase that negatively regulates mitogen-activated protein kinase (MAPK) signaling. In vivo deletion of an essential autophagy-related gene in T cells delayed the onset of and decreased the severity of experimental autoimmune encephalomyelitis. Our data support that autophagy may be necessary for T helper cell activation by regulating signaling pathways and metabolic programs, and the inhibition of this catabolic process may induce tolerance.