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

Thaiz Rivera Vargas, Zhijian Cai, Yingying Shen, Magalie Dosset, Isis Benoit-Lizon, Tiffany Martin, Aurélie Roussey, Richard A. Flavell, François Ghiringhelli () and Lionel Apetoh ()
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Thaiz Rivera Vargas: INSERM
Zhijian Cai: Zhejiang University School of Medicine
Yingying Shen: Zhejiang University School of Medicine
Magalie Dosset: INSERM
Isis Benoit-Lizon: INSERM
Tiffany Martin: INSERM
Aurélie Roussey: INSERM
Richard A. Flavell: Yale University School of Medicine
François Ghiringhelli: INSERM
Lionel Apetoh: INSERM

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00468-w

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