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 journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)592-607
Number of pages15
JournalDevelopmental Cell
Volume47
Issue number5
DOIs
Publication statusPublished - Dec 3 2018

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T-cells
Regulatory T-Lymphocytes
Cell Differentiation
Homeostasis
Complex networks
Transcription
Phosphoric Monoester Hydrolases
Modulators
Tumors
Transcription Factors
Disease Susceptibility
Autophagy
Autoimmune Diseases
Multiple Sclerosis
Maintenance
T-Lymphocytes
Proteins
Growth
Neoplasms

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AMBRA1 Controls Regulatory T-Cell Differentiation and Homeostasis Upstream of the FOXO3-FOXP3 Axis. / Becher, Juliane; Simula, Luca; Volpe, Elisabetta; Procaccini, Claudio; La Rocca, Claudia; D'Acunzo, Pasquale; Cianfanelli, Valentina; Strappazzon, Flavie; Caruana, Ignazio; Nazio, Francesca; Weber, Gerrit; Gigantino, Vincenzo; Botti, Gerardo; Ciccosanti, Fabiola; Borsellino, Giovanna; Campello, Silvia; Mandolesi, Georgia; De Bardi, Marco; Fimia, Gian Maria; D'Amelio, Marcello; Ruffini, Francesca; Furlan, Roberto; Centonze, Diego; Martino, Gianvito; Braghetta, Paola; Chrisam, Martina; Bonaldo, Paolo; Matarese, Giuseppe; Locatelli, Franco; Battistini, Luca; Cecconi, Francesco.

In: Developmental Cell, Vol. 47, No. 5, 03.12.2018, p. 592-607.

Research output: Contribution to journalArticle

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abstract = "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.",
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AU - Procaccini, Claudio

AU - La Rocca, Claudia

AU - D'Acunzo, Pasquale

AU - Cianfanelli, Valentina

AU - Strappazzon, Flavie

AU - Caruana, Ignazio

AU - Nazio, Francesca

AU - Weber, Gerrit

AU - Gigantino, Vincenzo

AU - Botti, Gerardo

AU - Ciccosanti, Fabiola

AU - Borsellino, Giovanna

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AU - De Bardi, Marco

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AU - D'Amelio, Marcello

AU - Ruffini, Francesca

AU - Furlan, Roberto

AU - Centonze, Diego

AU - Martino, Gianvito

AU - Braghetta, Paola

AU - Chrisam, Martina

AU - Bonaldo, Paolo

AU - Matarese, Giuseppe

AU - Locatelli, Franco

AU - Battistini, Luca

AU - Cecconi, Francesco

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