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.

Becher, J., Simula, L., Volpe, E., Procaccini, C., La Rocca, C., D'Acunzo, P., et al. (2018). AMBRA1 Controls Regulatory T-Cell Differentiation and Homeostasis Upstream of the FOXO3-FOXP3 Axis. DEVELOPMENTAL CELL, 47(5), 592-607.e6 [10.1016/j.devcel.2018.11.010].

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

Simula L.;Volpe E.;D'Acunzo P.;CIANFANELLI, VALENTINA;Caruana I.;Campello S.;De Bardi M.;D'Amelio M.;Centonze D.;Cecconi F.
2018

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.
Online ahead of print
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/06
English
PP2A; autophagy; experimental autoimmune encephalomyelitis; immune surveillance; multiple sclerosis; regulatory T cell
Becher, J., Simula, L., Volpe, E., Procaccini, C., La Rocca, C., D'Acunzo, P., et al. (2018). AMBRA1 Controls Regulatory T-Cell Differentiation and Homeostasis Upstream of the FOXO3-FOXP3 Axis. DEVELOPMENTAL CELL, 47(5), 592-607.e6 [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
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/207039
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