Systemic hypoxia or Foxp3-directed Phd2 silencing cause immune activation and augment the protective immune response to BCG
Abstract Hypoxia has widespread physiological effects, many of which are mediated through decreased activity of prolyl hydroxylase domain-2 (Phd2) which is the major oxygen-sensing hydroxylase controlling the hypoxia-inducible factor (HIF) transcriptional pathways. Here we demonstrate that in mice Phd2 silencing restricted to regulatory T cells or environmental hypoxic exposure can lead to the development of autoimmunity as evidenced by peripheral lymphadenopathy with multi-lineage leukocyte expansion and the development of anti-nuclear antibodies. Furthermore, the immune activation triggered by these manipulations can be harnessed to enhance the response to Bacillus Calmette-Guérin (BCG) immunisation, as measured by an ex vivo mycobacterial growth inhibition assay. The effects of Phd2 silencing and hypoxia are both mitigated in Hif-2alpha deficient mice. However, loss of Hif-1alpha (alone or in combination with Hif-2alpha) provokes an accentuated phenotype in response to hypoxia.
Authors
- Tammie Bishop (ORCID: https://orcid.org/0000-0003-3308-9139)
- Marie Sion
- Maria Prange‐Barczynska (ORCID: https://orcid.org/0000-0002-5378-5994)
- Christopher William Pugh (ORCID: https://orcid.org/0000-0002-5170-1662)
- Hisashi Hashimoto (ORCID: https://orcid.org/0000-0003-0089-9717)
- Aneesha Bhandari
- Kento Kawai (ORCID: https://orcid.org/0000-0003-2019-7210)
- Elena Stylianou (ORCID: https://orcid.org/0000-0002-1384-9367)
- Rachel Tanner (ORCID: https://orcid.org/0000-0003-3622-5984)
- Fadi Issa (ORCID: https://orcid.org/0000-0002-8279-7732)
- Alexandra J. Spencer (ORCID: https://orcid.org/0000-0001-7958-6961)
- Joanna Hester (ORCID: https://orcid.org/0000-0002-7466-3849)
- Oliver McCallion (ORCID: https://orcid.org/0000-0002-5977-812X)
- Tanya L. Crockford (ORCID: https://orcid.org/0009-0009-2343-4841)
- Peter John Ratcliffe (ORCID: https://orcid.org/0000-0002-2853-806X)
- Masateru Uchiyama (ORCID: https://orcid.org/0000-0002-7294-6706)
- Katherine R. Bull (ORCID: https://orcid.org/0000-0003-0656-0917)
- Thomas Riffelmacher (ORCID: https://orcid.org/0000-0002-0372-5272)
- Philip S. Macklin (ORCID: https://orcid.org/0000-0002-7750-3242)
- Helen McShane (ORCID: https://orcid.org/0000-0002-2126-5142)
- Nawamin Pinpathomrat (ORCID: https://orcid.org/0000-0002-0776-595X)
- Samvid Kurlekar (ORCID: https://orcid.org/0000-0003-1633-1827)
- Atsushi Yamamoto
Publication Details
- Journal
- Communications Biology
- Published
- 2026-09-24
- DOI
- https://doi.org/10.1038/s42003-026-10829-1
- Primary Topic
- Cancer, Hypoxia, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.00