Graded Foxo1 activity in T(reg) cells differentiates tumour immunity from spontaneous autoimmunity Journal Article


Authors: Luo, C. T.; Liao, W.; Dadi, S.; Toure, A.; Li, M. O.
Article Title: Graded Foxo1 activity in T(reg) cells differentiates tumour immunity from spontaneous autoimmunity
Abstract: Regulatory T (Treg) cells expressing the transcription factor Foxp3 have a pivotal role in maintaining immunological self-tolerance; yet, excessive Treg cell activities suppress anti-tumour immune responses. Compared to the resting Treg (rTreg) cell phenotype in secondary lymphoid organs, Treg cells in non-lymphoid tissues exhibit an activated Treg (aTreg) cell phenotype. However, the function of aTreg cells and whether their generation can be manipulated are largely unexplored. Here we show that the transcription factor Foxo1, previously demonstrated to promote Treg cell suppression of lymphoproliferative diseases, has an unexpected function in inhibiting aTreg-cell-mediated immune tolerance in mice. We find that aTreg cells turned over at a slower rate than rTreg cells, but were not locally maintained in tissues. aTreg cell differentiation was associated with repression of Foxo1-dependent gene transcription, concomitant with reduced Foxo1 expression, cytoplasmic localization and enhanced phosphorylation at the Akt sites. Treg-cell-specific expression of an Akt-insensitive Foxo1 mutant prevented downregulation of lymphoid organ homing molecules, and impeded Treg cell homing to non-lymphoid organs, causing CD8+ T-cell-mediated autoimmune diseases. Compared to Treg cells from healthy tissues, tumour-infiltrating Treg cells downregulated Foxo1 target genes more substantially. Expression of the Foxo1 mutant at a lower dose was sufficient to deplete tumour-associated Treg cells, activate effector CD8+ T cells, and inhibit tumour growth without inflicting autoimmunity. Thus, Foxo1 inactivation is essential for the migration of aTreg cells that have a crucial function in suppressing CD8+ T-cell responses; and the Foxo signalling pathway in Treg cells can be titrated to break tumour immune tolerance preferentially. © 2016 Macmillan Publishers Limited. All rights reserved.
Keywords: signal transduction; controlled study; human cell; genetics; mutation; nonhuman; cancer patient; neoplasm; neoplasms; cd8+ t lymphocyte; tumor associated leukocyte; cd8-positive t-lymphocytes; forkhead transcription factors; lymphocytes, tumor-infiltrating; animal cell; mouse; phenotype; animal; cytology; metabolism; animals; mice; mus; gene expression; gene expression profiling; down-regulation; cell motion; genetic transcription; cell differentiation; transcription, genetic; phosphorylation; alanine aminotransferase blood level; lymphocyte differentiation; immunological tolerance; regulatory t lymphocyte; biosynthesis; immunology; lymphocyte activation; immune tolerance; enzyme phosphorylation; immune response; t-lymphocytes, regulatory; genomic instability; gene repression; cell migration; cell movement; tumor immunity; autoimmunity; down regulation; tumor growth; forkhead transcription factor; t lymphocyte activation; lymphoid organ; liver injury; foxo1 protein, mouse; transcription factor fkhr; protein kinase b inhibitor; cancer prognosis; human; male; female; priority journal; article
Journal Title: Nature
Volume: 529
Issue: 7587
ISSN: 0028-0836
Publisher: Nature Publishing Group  
Date Published: 2016-01-28
Start Page: 532
End Page: 536
Language: English
DOI: 10.1038/nature16486
PUBMED: 26789248
PROVIDER: scopus
PMCID: PMC4978705
DOI/URL:
Notes: Article -- Export Date: 3 March 2016 -- Source: Scopus
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MSK Authors
  1. Ming Li
    106 Li
  2. Chong Luo
    9 Luo
  3. Saida   Dadi
    8 Dadi
  4. Ahmed   Toure
    7 Toure