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

Dev Cell. 2018 Dec 3;47(5):592-607.e6. doi: 10.1016/j.devcel.2018.11.010.

Juliane Becher ¹, Luca Simula ², Elisabetta Volpe ¹, Claudio Procaccini ³, Claudia La Rocca ⁴, Pasquale D'Acunzo ², Valentina Cianfanelli ⁵, Flavie Strappazzon ⁶, Ignazio Caruana ², Francesca Nazio ², Gerrit Weber ², Vincenzo Gigantino ⁷, Gerardo Botti ⁷, Fabiola Ciccosanti ⁸, Giovanna Borsellino ¹, Silvia Campello ⁶, Georgia Mandolesi ¹, Marco De Bardi ¹, Gian Maria Fimia ⁹, Marcello D'Amelio ¹⁰, Francesca Ruffini ¹¹, Roberto Furlan ¹¹, Diego Centonze ¹², Gianvito Martino ¹¹, Paola Braghetta ¹³, Martina Chrisam ¹³, Paolo Bonaldo ¹⁴, Giuseppe Matarese ¹⁵, Franco Locatelli ¹⁶, Luca Battistini ¹, Francesco Cecconi ¹⁷

Affiliations

1 IRCCS Fondazione Santa Lucia, Rome 00143, Italy.
2 Department of Pediatric Hemato-Oncology and cell and gene therapy, IRCCS Bambino Gesù Children's Hospital, Rome 00143, Italy.
3 IRCCS Fondazione Santa Lucia, Rome 00143, Italy; Istituto per l'Endocrinologia e l'Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), Naples 80131, Italy.
4 Istituto per l'Endocrinologia e l'Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), Naples 80131, Italy.
5 Unit of Cell Stress and Survival, Danish Cancer Society Research Center, Copenhagen 2100, Denmark.
6 IRCCS Fondazione Santa Lucia, Rome 00143, Italy; Department of Biology, University of Rome Tor Vergata, Rome 00133, Italy.
7 Unità di Patologia, Istituto Nazionale Tumori Fondazione "G. Pascale", Naples, Italy.
8 National Institute for Infectious Diseases IRCCS "L Spallanzani", Rome 00149, Italy.
9 National Institute for Infectious Diseases IRCCS "L Spallanzani", Rome 00149, Italy; Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, Lecce 73100, Italy.
10 IRCCS Fondazione Santa Lucia, Rome 00143, Italy; University Campus Bio-Medico, Rome, Italy.
11 Dipartimento di Ricerca Biologica e Tecnologia, Istituto Scientifico San Raffaele, Milan, Italy.
12 Department of Systems Medicine, University of Rome Tor Vergata, Rome 00133, Italy; Unit of Neurology and of Neurorehabilitation, IRCCS Neuromed, Pozzilli 86077 (IS), Italy.
13 Department of Molecular Medicine, Università Degli Studi di Padova, Padova 35131, Italy.
14 Department of Molecular Medicine, Università Degli Studi di Padova, Padova 35131, Italy; CRIBI Biotechnology Center, Università Degli Studi di Padova, Padova 35131, Italy.
15 Istituto per l'Endocrinologia e l'Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), Naples 80131, Italy; Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II", Naples, Italy.
16 Department of Pediatric Hemato-Oncology and cell and gene therapy, IRCCS Bambino Gesù Children's Hospital, Rome 00143, Italy; Department of Gynecology/Obstetrics and Pediatrics, Sapienza University of Rome, Italy.
17 IRCCS Fondazione Santa Lucia, Rome 00143, Italy; Unit of Cell Stress and Survival, Danish Cancer Society Research Center, Copenhagen 2100, Denmark; Department of Biology, University of Rome Tor Vergata, Rome 00133, Italy. Electronic address: cecconi@cancer.dk.

PMID: 30513302 DOI: 10.1016/j.devcel.2018.11.010

Abstract

Regulatory T cells (T_reg) 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 T_reg 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 T_reg 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 T_reg cell induction in mouse models of both tumor growth and multiple sclerosis, thus highlighting the role of AMBRA1 in the control of immune homeostasis.

Keywords

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

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