Abstract
Hypoxia-inducible factor 1α (HIF-1α) and HIF-2α are master transcription factors that regulate cellular responses to hypoxia, but the exact function in regulatory T (Treg) cells is controversial. Here, we show that Treg cell development is normal in mice with Foxp3-specific knockout (KO) of HIF-1α or HIF-2α. However, HIF-2α-KO (but not HIF-1α-KO) Treg cells are functionally defective in suppressing effector T cell-induced colitis and inhibiting airway hypersensitivity. HIF-2α-KO Treg cells have enhanced reprogramming into IL-17-secreting cells. We show crosstalk between HIF-2α and HIF-1α, and that HIF-2α represses HIF-1α expression. HIF-1α is upregulated in HIF-2α-KO Treg cells and further deletion of HIF-1α restores the inhibitory function of HIF-2α-KO Treg cells. Mice with Foxp3-conditional KO of HIF-2α are resistant to growth of MC38 colon adenocarcinoma and metastases of B16F10 melanoma. Together, these results indicate that targeting HIF-2α to destabilize Treg cells might be an approach for regulating the functional activity of Treg cells.
Highlights
Hypoxia-inducible factor 1α (HIF-1α) and HIF-2α are master transcription factors that regulate cellular responses to hypoxia, but the exact function in regulatory T (Treg) cells is controversial
T cell proliferation, IL-2 production, and IFN-γ generation stimulated through CD3/CD28 were normal in Cd4CreHif2af/f T cells isolated from lymph nodes and spleen (Supplementary Fig. 3)
We observed a similar outcome for T cell development in Foxp3CreHif2af/f mice (Supplementary Fig. 4)
Summary
Hypoxia-inducible factor 1α (HIF-1α) and HIF-2α are master transcription factors that regulate cellular responses to hypoxia, but the exact function in regulatory T (Treg) cells is controversial. Mice with Foxp3-conditional KO of HIF-2α are resistant to growth of MC38 colon adenocarcinoma and metastases of B16F10 melanoma Together, these results indicate that targeting HIF-2α to destabilize Treg cells might be an approach for regulating the functional activity of Treg cells. Treg cells are characterized by their expression of the master transcription factor forkhead box P3 (Foxp3), which dictates their development and function[2,3,4]. Some Treg cells are converted into inflammatory effector cells following Foxp[3] destabilization, which may lead to loss of their suppressive activity and expression of inflammatory cytokines such as IFN-γ or IL-17 In the presence of O2, HIF-1α and HIF-2α are hydroxylated at key proline residues by prolyl hydroxylase domain protein 2 (PHD2)/PHD3, leading to recognition by the von Hippel-Lindau (VHL)-containing E3 complex that ubiquitinates
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