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

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

Author information

1
Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Center for Molecular Medicine, University Medical Center Utrecht, 3584 Utrecht, the Netherlands. Electronic address: e.mocholi-gimeno@umcutrecht.nl.
2
Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
3
Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
4
Department of Pediatric Immunology, University Medical Center Utrecht, 3584 Utrecht, the Netherlands.
5
Center for Molecular Medicine, University Medical Center Utrecht, 3584 Utrecht, the Netherlands.
6
Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address: fernando.macian@einstein.yu.edu.

Abstract

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

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