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. Regulatory T cells (T reg ) maintain immunological tolerance and help control autoimmune disease susceptibility. Becher et al. show pro-autophagy factor AMBRA1 regulates human and mouse T reg 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. © 2018 Elsevier Inc.

AMBRA1 Controls Regulatory T-Cell Differentiation and Homeostasis Upstream of the FOXO3-FOXP3 Axis / Becher, J.; Simula, L.; Volpe, E.; Procaccini, C.; La Rocca, C.; D'Acunzo, P.; Cianfanelli, V.; Strappazzon, F.; Caruana, I.; Nazio, F.; Weber, G.; Gigantino, V.; Botti, G.; Ciccosanti, F.; Borsellino, G.; Campello, S.; Mandolesi, G.; De Bardi, M.; Fimia, G. M.; D'Amelio, M.; Ruffini, F.; Furlan, R.; Centonze, D.; Martino, G.; Braghetta, P.; Chrisam, M.; Bonaldo, P.; Matarese, G.; Locatelli, F.; Battistini, L.; Cecconi, F.. - In: DEVELOPMENTAL CELL. - ISSN 1534-5807. - 47:5(2018), pp. 592-607.e6. [10.1016/j.devcel.2018.11.010]

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

Fimia, G. M.;Locatelli, F.;
2018

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. Regulatory T cells (T reg ) maintain immunological tolerance and help control autoimmune disease susceptibility. Becher et al. show pro-autophagy factor AMBRA1 regulates human and mouse T reg 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. © 2018 Elsevier Inc.
2018
AMBRA1 protein; autophagy related protein; phosphatase; PP2A protein; transcription factor FKHRL1; transcription factor FOXP3; unclassified drug; AMBRA1 protein, human; forkhead transcription factor; FOXO3 protein, human; FOXP3 protein, human; phosphoprotein phosphatase 2; signal transducing adaptor protein; transcription factor FKHRL1, animal experiment; animal model; Article; homeostasis and regulation; immune response; immunoregulation; in vitro study; in vivo study; lymphocyte differentiation; mouse; multiple sclerosis; nonhuman; priority journal; protein defect; protein protein interaction; receptor upregulation; regulatory T lymphocyte; tumor growth; animal; C57BL mouse; cell culture; cell differentiation; cytology; genetics; HeLa cell line; homeostasis; human; Jurkat cell line; metabolism; T lymphocyte, Adaptor Proteins, Signal Transducing; Animals; Cell Differentiation; Cells, Cultured; Forkhead Box Protein O3; Forkhead Transcription Factors; HeLa Cells; Homeostasis; Humans; Jurkat Cells; Mice; Mice, Inbred C57BL; Multiple Sclerosis; Protein Phosphatase 2; T-Lymphocytes; autophagy; experimental autoimmune encephalomyelitis; immune surveillance; multiple sclerosis; PP2A; regulatory T cell
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AMBRA1 Controls Regulatory T-Cell Differentiation and Homeostasis Upstream of the FOXO3-FOXP3 Axis / Becher, J.; Simula, L.; Volpe, E.; Procaccini, C.; La Rocca, C.; D'Acunzo, P.; Cianfanelli, V.; Strappazzon, F.; Caruana, I.; Nazio, F.; Weber, G.; Gigantino, V.; Botti, G.; Ciccosanti, F.; Borsellino, G.; Campello, S.; Mandolesi, G.; De Bardi, M.; Fimia, G. M.; D'Amelio, M.; Ruffini, F.; Furlan, R.; Centonze, D.; Martino, G.; Braghetta, P.; Chrisam, M.; Bonaldo, P.; Matarese, G.; Locatelli, F.; Battistini, L.; Cecconi, F.. - In: DEVELOPMENTAL CELL. - ISSN 1534-5807. - 47:5(2018), pp. 592-607.e6. [10.1016/j.devcel.2018.11.010]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1411034
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