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

Cell Rep. 2018 Jul 31;24(5):1136-1150. doi: 10.1016/j.celrep.2018.06.065.


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.

Keywords: T cell; anergy; autoimmunity; autophagy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy*
  • CD4-Positive T-Lymphocytes / immunology*
  • Cells, Cultured
  • Clonal Anergy*
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / metabolism
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism
  • Receptors, Antigen, T-Cell / metabolism


  • Receptors, Antigen, T-Cell
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Ptpn1 protein, mouse