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

Enric Mocholi, Samuel D. Dowling, Yair M. Botbol, Ross C. Gruber, Alex K. Ray, Sebastiaan Vastert, Bridget Shafit-Zagardo, Paul J. Coffer, Fernando Macian-Juan

Research output: Contribution to journalArticle

4 Citations (Scopus)

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. Mocholi et al. show that, following T cell activation, activation of autophagy constitutes a tolerance-avoidance mechanism that, through modulation of cell metabolism and specific signaling pathways, allows T cells to engage in effector responses and avoid anergy. In vivo inhibition of autophagy in T cells induces tolerance and prevents autoimmunity.

Original languageEnglish (US)
Pages (from-to)1136-1150
Number of pages15
JournalCell Reports
Volume24
Issue number5
DOIs
StatePublished - Jul 31 2018

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T-cells
Autophagy
T-Cell Antigen Receptor
Metabolism
T-Lymphocytes
Chemical activation
Up-Regulation
Protein Tyrosine Phosphatases
Juvenile Arthritis
Autoimmune Experimental Encephalomyelitis
Synovial Fluid
Autoimmunity
Transcriptome
Genes
Modulation
Respiration
Antigens
Fluids

Keywords

  • anergy
  • autoimmunity
  • autophagy
  • T cell

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Autophagy Is a Tolerance-Avoidance Mechanism that Modulates TCR-Mediated Signaling and Cell Metabolism to Prevent Induction of T Cell Anergy. / Mocholi, Enric; Dowling, Samuel D.; Botbol, Yair M.; Gruber, Ross C.; Ray, Alex K.; Vastert, Sebastiaan; Shafit-Zagardo, Bridget; Coffer, Paul J.; Macian-Juan, Fernando.

In: Cell Reports, Vol. 24, No. 5, 31.07.2018, p. 1136-1150.

Research output: Contribution to journalArticle

Mocholi, Enric ; Dowling, Samuel D. ; Botbol, Yair M. ; Gruber, Ross C. ; Ray, Alex K. ; Vastert, Sebastiaan ; Shafit-Zagardo, Bridget ; Coffer, Paul J. ; Macian-Juan, Fernando. / Autophagy Is a Tolerance-Avoidance Mechanism that Modulates TCR-Mediated Signaling and Cell Metabolism to Prevent Induction of T Cell Anergy. In: Cell Reports. 2018 ; Vol. 24, No. 5. pp. 1136-1150.
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