TY - JOUR
T1 - AMBRA1 Controls Regulatory T-Cell Differentiation and Homeostasis Upstream of the FOXO3-FOXP3 Axis
AU - Becher, Juliane
AU - Simula, Luca
AU - Volpe, Elisabetta
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
AU - Campello, Silvia
AU - Mandolesi, Georgia
AU - De Bardi, Marco
AU - Fimia, Gian Maria
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
PY - 2018/12/3
Y1 - 2018/12/3
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.
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.
KW - autophagy
KW - experimental autoimmune encephalomyelitis
KW - immune surveillance
KW - multiple sclerosis
KW - PP2A
KW - regulatory T cell
UR - http://www.scopus.com/inward/record.url?scp=85056817150&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85056817150&partnerID=8YFLogxK
U2 - 10.1016/j.devcel.2018.11.010
DO - 10.1016/j.devcel.2018.11.010
M3 - Article
AN - SCOPUS:85056817150
SP - 592
EP - 607
JO - Developmental Cell
JF - Developmental Cell
SN - 1534-5807
ER -