Deltex1 antagonizes HIF-1 alpha and sustains the stability of regulatory T cells in vivo
Resource
Nat. Commun., 6,
Journal
Nat. Commun.
Journal Issue
6
Pages
-
Date Issued
2015
Date
2015
Author(s)
Hsiao, Huey-Wen
Hsu, Tzu-Sheng
Liu, Wen-Hsien
Hsieh, Wan-Chen
Chou, Ting-Fang
Wu, Yu-Jung
Jiang, Si-Tse
Lai, Ming-Zong
Abstract
Application of regulatory Tcells (Tregs) in transplantation, autoimmunity and allergy has been extensively explored, but how Foxp3 and Treg stability is regulated in vivo is incompletely understood. Here, we identify a requirement for Deltex1 (DTX1), a contributor to T-cell anergy and Foxp3 protein level maintenance in vivo. Dtx1(-/-) Tregs are as effective as WT Tregs in the inhibition of CD4(+) CD25(-) T-cell activation in vitro. However, the suppressive ability of Dtx1(-/-) Tregs is greatly impaired in vivo. We find that Foxp3 expression is diminished when Dtx1(-/-) Tregs are co-transferred with effector Tcells in vivo. DTX1 promotes the degradation of HIF-1 alpha. Knockout of HIF-1 alpha restores the Foxp3 stability and rescues the defective suppressive activity in Dtx1(-/-) Treg cells in vivo. Our results suggest that DTX1 exerts another level of control on Treg stability in vivo by sustaining the expression of Foxp3 protein in Tregs.
SDGs
Other Subjects
Deltex1 protein; hypoxia inducible factor 1alpha; suppressor factor; transcription factor FOXP3; ubiquitin protein ligase E3; unclassified drug; DNA binding protein; Dtx1 protein, mouse; forkhead transcription factor; Foxp3 protein, mouse; Hif1a protein, mouse; hypoxia inducible factor 1alpha; allergy; cell organelle; gene expression; protein; stabilization; animal cell; animal experiment; animal model; Article; CD4+ CD25+ T lymphocyte; cell specificity; clonal anergy; controlled study; female; gene deletion; gene inactivation; human; human cell; in vitro study; in vivo study; male; molecular stability; mouse; nonhuman; protein degradation; protein expression; protein function; protein protein interaction; protein stability; regulatory T lymphocyte; T lymphocyte activation; treatment failure; animal; C57BL mouse; hypersensitivity; immunology; inflammatory bowel disease; knockout mouse; lymphocyte activation; metabolism; physiology; regulatory T lymphocyte; Animals; DNA-Binding Proteins; Female; Forkhead Transcription Factors; Hypersensitivity; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammatory Bowel Diseases; Lymphocyte Activation; Mice, Inbred C57BL; Mice, Knockout; T-Lymphocytes, Regulatory