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

J Becher, L Simula, E Volpe, C Procaccini, C La Rocca, P D'Acunzo, V Cianfanelli, F Strappazzon, I Caruana, F Nazio, G Weber, V Gigantino, G Botti, F Ciccosanti, G Borsellino, S Campello, G Mandolesi, M De Bardi, GM Fimia, M D'AmelioF Ruffini, R Furlan, D Centonze, G Martino, P Braghetta, M Chrisam, P Bonaldo, G Matarese, F Locatelli, L Battistini, F 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. 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. © 2018 Elsevier Inc.
Original languageEnglish
Pages (from-to)592-607.e6
JournalDevelopmental Cell
Volume47
Issue number5
DOIs
Publication statusPublished - 2018

Fingerprint

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

Cite this

Becher, J., Simula, L., Volpe, E., Procaccini, C., La Rocca, C., D'Acunzo, P., ... Cecconi, F. (2018). AMBRA1 Controls Regulatory T-Cell Differentiation and Homeostasis Upstream of the FOXO3-FOXP3 Axis. Developmental Cell, 47(5), 592-607.e6. https://doi.org/10.1016/j.devcel.2018.11.010

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, GM; 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, Vol. 47, No. 5, 2018, p. 592-607.e6.

Research output: Contribution to journalArticle

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, GM, 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 2018, 'AMBRA1 Controls Regulatory T-Cell Differentiation and Homeostasis Upstream of the FOXO3-FOXP3 Axis', Developmental Cell, vol. 47, no. 5, pp. 592-607.e6. https://doi.org/10.1016/j.devcel.2018.11.010
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, GM ; 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. / AMBRA1 Controls Regulatory T-Cell Differentiation and Homeostasis Upstream of the FOXO3-FOXP3 Axis. In: Developmental Cell. 2018 ; Vol. 47, No. 5. pp. 592-607.e6.
@article{d9928e6ac3de4f15bf65b43afd4568fa,
title = "AMBRA1 Controls Regulatory T-Cell Differentiation and Homeostasis Upstream of the FOXO3-FOXP3 Axis",
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. 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. {\circledC} 2018 Elsevier Inc.",
author = "J Becher and L Simula and E Volpe and C Procaccini and {La Rocca}, C and P D'Acunzo and V Cianfanelli and F Strappazzon and I Caruana and F Nazio and G Weber and V Gigantino and G Botti and F Ciccosanti and G Borsellino and S Campello and G Mandolesi and {De Bardi}, M and GM Fimia and M D'Amelio and F Ruffini and R Furlan and D Centonze and G Martino and P Braghetta and M Chrisam and P Bonaldo and G Matarese and F Locatelli and L Battistini and F Cecconi",
year = "2018",
doi = "10.1016/j.devcel.2018.11.010",
language = "English",
volume = "47",
pages = "592--607.e6",
journal = "Developmental Cell",
issn = "1534-5807",
publisher = "Cell Press",
number = "5",

}

TY - JOUR

T1 - AMBRA1 Controls Regulatory T-Cell Differentiation and Homeostasis Upstream of the FOXO3-FOXP3 Axis

AU - Becher, J

AU - Simula, L

AU - Volpe, E

AU - Procaccini, C

AU - La Rocca, C

AU - D'Acunzo, P

AU - Cianfanelli, V

AU - Strappazzon, F

AU - Caruana, I

AU - Nazio, F

AU - Weber, G

AU - Gigantino, V

AU - Botti, G

AU - Ciccosanti, F

AU - Borsellino, G

AU - Campello, S

AU - Mandolesi, G

AU - De Bardi, M

AU - Fimia, GM

AU - D'Amelio, M

AU - Ruffini, F

AU - Furlan, R

AU - Centonze, D

AU - Martino, G

AU - Braghetta, P

AU - Chrisam, M

AU - Bonaldo, P

AU - Matarese, G

AU - Locatelli, F

AU - Battistini, L

AU - Cecconi, F

PY - 2018

Y1 - 2018

N2 - 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. © 2018 Elsevier Inc.

AB - 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. © 2018 Elsevier Inc.

U2 - 10.1016/j.devcel.2018.11.010

DO - 10.1016/j.devcel.2018.11.010

M3 - Article

VL - 47

SP - 592-607.e6

JO - Developmental Cell

JF - Developmental Cell

SN - 1534-5807

IS - 5

ER -