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

2018

DEVELOPMENTAL CELL

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

01 Pubblicazione su rivista

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.

DOI: 10.1016/j.devcel.2018.11.010

ISSN: 1534-5807

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 protein AMBRA1 protein Human animal animal model autophagy autophagy related protein C57BL mouse cell culture cell differentiation cytology Forkhead Box Protein O3 forkhead transcription factor Forkhead Transcription Factors FOXO3 protein Human FOXP3 protein Human HeLa cell line HeLa cells homeostasis homeostasis and regulation Human immune response immune surveillance immunoregulation in vitro study in vivo study Jurkat cell line lymphocyte differentiation Mice Mice Inbred C57BL multiple sclerosis nonhuman phosphatase phosphoprotein phosphatase 2 PP2A PP2A protein priority journal protein defect Protein Phosphatase 2 protein protein interaction receptor upregulation regulatory T lymphocyte signal transducing adaptor protein T lymphocyte Adaptor Proteins Signal Transducing transcription factor FKHRL1 transcription factor FKHRL1 animal experiment transcription factor FOXP3 tumor growth unclassified drug