Autophagy Is a Tolerance-Avoidance Mechanism that Modulates TCR-Mediated Signaling and Cell Metabolism to Prevent Induction of T Cell Anergy.

In response to activation, CD4+ T cells upregulate autophagy. However, the functional consequences of that upregulation have not been fully elucidated. In this study, we identify autophagy as a tolerance-avoidance mechanism. Our data show that inhibition of autophagy during CD4+ T cell activation induces a long-lasting state of hypo-responsiveness that is accompanied by the expression of an anergic gene signature. Cells unable to induce autophagy after T cell receptor (TCR) engagement show inefficient mitochondrial respiration and decreased turnover of the protein tyrosine phosphatase PTPN1, which translates into defective TCR-mediated signaling. In vivo, inhibition of autophagy during antigen priming induces T cell anergy and decreases the severity of disease in an experimental autoimmune encephalomyelitis mouse model. Interestingly, CD4+ T cells isolated from the synovial fluid of juvenile idiopathic arthritis patients, while resistant to suboptimal stimulation-induced anergy, can be tolerized with autophagy inhibitors. We propose that autophagy constitutes a tolerance-avoidance mechanism, which determines CD4+ T cell fate.

Autophagy and T cell metabolism.

Autophagy, a highly conserved catabolic process that involves the degradation and recycling of intracellular components in the lysosome, has emerged as a key process in the maintenance of T cell homeostasis and the regulation of T cell differentiation and function. In this review, we provide an overview of the mechanisms that mediate the regulation of autophagy in T cells and discuss different cellular processes that are under the control of autophagy in CD4+ and CD8+ T cells. A special emphasis is placed on the role that autophagy plays in the modulation of T cell metabolism and the consequences of this regulation on functional states and programs of differentiation in specific T cell populations.