Deltex1 antagonizes HIF-1α and sustains the stability of regulatory T cells in vivo

Abstract

Application of regulatory T cells (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 T cells in vivo. DTX1 promotes the degradation of HIF-1α. Knockout of HIF-1α 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.

Hypoxia-inducible factors regulate T cell metabolism and function

“…In addition to driving expression of T H 17 signature genes, HIF-1α also inhibited differentiation of iT reg by binding to Foxp3 through a n-terminal domain resulting in proteosomal degradation of Foxp3 in spite of TGF-β signaling present in in vitro T H 17 culture conditions [23]. Additional studies by several groups in human and murine models, have both supported and contradicted aspects of these initial reports [70–75]. It is clear that HIF-1α can play a role in the differentiation of T H 17 versus iT reg cells.…”

Ubiquitin‐dependent regulation of Foxp3 and Treg function

“…Instead, it was found to bind HIF‐1, promoting hydroxylation of proline residues. The authors also showed that DTX expression could prevent hypoxia‐induced reduction in the Foxp3 protein pool in T cells . These results do not appear at first glance to support a model for Foxp3–HIF‐1 co‐degradation via the proteasome as, in the absence of DTX1, Foxp3 protein loss was more pronounced alongside reduced HIF‐1 degradation.…”

“…This deficiency was attributed to unstable expression of Foxp3 seen alongside the elevated HIF‐1 levels in the absence of DTX1. Importantly, the authors showed that simultaneous HIF‐1 and DTX1 deficiency in Tregs restored their in vivo Foxp3 expression level and largely corrected the inability of DTX1‐deficient Tregs to prevent colitis . Interestingly, DTX1 did not appear to drive the direct ubiquitination of HIF‐1.…”

“…Inflammatory cues including proinflammatory cytokines (IL-6, TNFa) have been reported to drive dephosphorylation and degradative polyubiquitination of Foxp3 (82, 108) while counteracting the Foxp3-stabilizing/ enhancing acetylation modifications (77). Certain 'danger signals', including microbial products and stresses (LPS, heat shock, hypoxia), also appear to engage pathways leading to post-translational down modulation of Foxp3 expression and Treg function (107,108,124).…”

Deltex-1 mutations predict poor survival in diffuse large B-cell lymphoma

“…Interestingly, in the hematological context, DTX1 can negatively regulate T-cell activation by targeting mitogen-activated protein kinase kinase kinase 1 (MEKK1 or MAP3K) and protein kinase C Θ for degradation, 8,9 and mediate degradation of hypoxia-inducible factor-1α (HIF-1α) in regulatory T cells (Tregs). 10 However, in normal B cells and lymphomas, the function of DTX1 and the impact of mutations remain to be established. Somatic hypermutation has been predicted to aberrantly target the DTX1 gene, 11 and DTX1 mutations have previously been reported in follicular and splenic marginal zone lymphomas.…”