Selective degradation of PU.1 during autophagy represses the differentiation and antitumour activity of T H 9 cells

• Published in: Nature communications Vol. 8; no. 1; p. 559
• Main Authors: Rivera Vargas, Thaiz, Cai, Zhijian, Shen, Yingying, Dosset, Magalie, Benoit-Lizon, Isis, Martin, Tiffany, Roussey, Aurélie, Flavell, Richard A, Ghiringhelli, François, Apetoh, Lionel
• Format: Journal Article
• Language: English
• Published: England 15.09.2017
• Subjects: Animals; Autophagy - immunology; Autophagy-Related Protein 5; Autophagy-Related Proteins; Cell Differentiation - immunology; Immunotherapy; Interleukin-9 - immunology; Lymphopoiesis - immunology; Mice; Neoplasms - immunology; Neoplasms - therapy; Proto-Oncogene Proteins - metabolism; T-Lymphocyte Subsets - immunology; T-Lymphocytes, Helper-Inducer - immunology; Trans-Activators - metabolism; Ubiquitin-Conjugating Enzymes
• ISSN: 2041-1723

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 (T 9) cell differentiation. CD4 T cells lacking Atg3 or Atg5 have increased interleukin-9 (IL-9) expression upon differentiation into T 9 cells relative to Atg3- or Atg5-expressing control cells. In addition, the T 9 cell transcription factor, PU.1, undergoes K63 ubiquitination and degradation through p62-dependent selective autophagy. Finally, the blockade of autophagy enhances T 9 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 T 9 cell differentiation and antitumour activity, and prompt potential autophagy-dependent modulations of T 9 activity for cancer immunotherapy.Autophagy is a cellular process for recycling cell constituents, and is essential for T cell activation, but its function in T cell polarization is still unclear. Here the authors show that autophagy induces the degradation of transcription factor PU.1 to negatively modulate T 9 homeostasis and antitumour immunity.