AMBRA1 Controls Regulatory T-Cell Differentiation and Homeostasis Upstream of the FOXO3-FOXP3 Axis

Juliane Becher, Luca Simula, Elisabetta Volpe, Claudio Procaccini, Claudia La Rocca, Pasquale D'Acunzo, Valentina Cianfanelli, Flavie Strappazzon, Ignazio Caruana, Francesca Nazio, Gerrit Weber, Vincenzo Gigantino, Gerardo Botti, Fabiola Ciccosanti, Giovanna Borsellino, Silvia Campello, Georgia Mandolesi, Marco De Bardi, Gian Maria Fimia, Marcello D'AmelioFrancesca Ruffini, Roberto Furlan, Diego Centonze, Gianvito Martino, Paola Braghetta, Martina Chrisam, Paolo Bonaldo, Giuseppe Matarese, Franco Locatelli, Luca Battistini, Francesco Cecconi

Research output: Contribution to journalArticlepeer-review


Regulatory T cells (Treg) are necessary to maintain immunological tolerance and are key players in the control of autoimmune disease susceptibility. Expression of the transcription factor FOXP3 is essential for differentiation of Treg cells and indispensable for their suppressive function. However, there is still a lack of knowledge about the mechanisms underlying its regulation. Here, we demonstrate that pro-autophagy protein AMBRA1 is also a key modulator of T cells, regulating the complex network that leads to human Treg differentiation and maintenance. Indeed, through its ability to interact with the phosphatase PP2A, AMBRA1 promotes the stability of the transcriptional activator FOXO3, which, in turn, triggers FOXP3 transcription. Furthermore, we found that AMBRA1 plays a significant role in vivo by regulating Treg cell induction in mouse models of both tumor growth and multiple sclerosis, thus highlighting the role of AMBRA1 in the control of immune homeostasis. Regulatory T cells (Treg) maintain immunological tolerance and help control autoimmune disease susceptibility. Becher et al. show pro-autophagy factor AMBRA1 regulates human and mouse Treg differentiation and maintenance. AMBRA1 is upregulated in stimulated T cells to stabilize FOXO3 and has a protective effect in a mouse model of multiple sclerosis.

Original languageEnglish
Pages (from-to)592-607
Number of pages16
JournalDevelopmental Cell
Publication statusPublished - Dec 3 2018


  • autophagy
  • experimental autoimmune encephalomyelitis
  • immune surveillance
  • multiple sclerosis
  • PP2A
  • regulatory T cell

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology


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