Work

Selective degradation of PU.1 during autophagy represses the differentiation and antitumour activity of TH9 cells

Year: 2017

Type: article

Abstract: Autophagy, a catabolic mechanism that involves degradation of cellular components, is essential for cell homeostasis. Although autophagy favours the lineage stability of regulatory T cells, the contribution of autophagy to the differentiation of effector CD4 T cells remains unclear. Here we show that autophagy selectively represses T helper 9 (TH9) cell differentiation. CD4 T cells lacking Atg3 or Atg5 have increased interleukin-9 (IL-9) expression upon differentiation into TH9 cells relative to Atg3- or Atg5-expressing control cells. In addition, the TH9 cell transcription factor, PU.1, undergoes K63 ubiquitination and degradation through p62-dependent selective autophagy. Finally, the blockade of autophagy enhances TH9 cell anticancer functions in vivo, and mice with T cell-specific deletion of Atg5 have reduced tumour outgrowth in an IL-9-dependent manner. Overall, our findings reveal an unexpected function of autophagy in the modulation of TH9 cell differentiation and antitumour activity, and prompt potential autophagy-dependent modulations of TH9 activity for cancer immunotherapy.

Source: Nature Communications

DOI: 10.1038/s41467-017-00468-w

Authors: Thaiz Rivera Vargas, Zhijian Cai, Yingying Shen, Magalie Dosset, Isis Benoit-Lizon, Tiffany Martin, Aurélie Roussey, Richard A. Flavell, François Ghiringhelli, Lionel Apetoh

Institutions: Inserm, Université de Bourgogne, Université Bourgogne Franche-Comté, Centre de recherche Translationnelle en Médecine moléculaire, Zhejiang University, Établissement Français du Sang, Howard Hughes Medical Institute, Yale University, Centre Georges François Leclerc

Language: English

Topic: T-cell and B-cell Immunology

Subfield: Immunology

Field: Immunology and Microbiology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,990

Funders: Fondation pour l'Aide à la Recherche sur la Sclérose en Plaques, European Commission, Agence Nationale de la Recherche, Fondation ARC pour la Recherche sur le Cancer, Fondation de France, Institut National Du Cancer, Conseil régional de Bourgogne-Franche-Comté, Institut Mérieux, National Institutes of Health, National Center for Advancing Translational Sciences, H2020 European Research Council

Awards: Molecular mechanisms controling IL-1ß-induced Th9 cell anticancer functions, Cell intrinsic control of CD4 T cell differentiation by cytosolic DNA sensing pathways, Lipoprotéines et santé : prévention et traitement des maladies inflammatoires non vasculaires et du cancer, Transcriptional regulation of IL-9-producing CD4 T cells: use in cancer immunotherapy, Yale Clinical and Translational Science Award

OpenAlex ID: W2754508153

FWCI: 4.35

Cites: 58

Cited by: 85

Related to: 10