TY - JOUR TI - The oxygen sensor prolyl hydroxylase domain 2 regulates the in vivo suppressive capacity of regulatory T cells AU - Ajouaou, Yousra AU - Azouz, Abdulkader AU - Taquin, Anaëlle AU - Denanglaire, Sebastien AU - Hussein, Hind AU - Krayem, Mohammad AU - Andris, Fabienne AU - Moser, Muriel AU - Goriely, Stanislas AU - Leo, Oberdan A2 - Ratcliffe, Peter J A2 - Zaidi, Mone A2 - Pugh, Chris A2 - Johnson, Randall VL - 11 PY - 2022 DA - 2022/02/22 SP - e70555 C1 - eLife 2022;11:e70555 DO - 10.7554/eLife.70555 UR - https://doi.org/10.7554/eLife.70555 AB - The oxygen sensor prolyl hydroxylase domain 2 (PHD2) plays an important role in cell hypoxia adaptation by regulating the stability of HIF proteins (HIF1α and HIF2α) in numerous cell types, including T lymphocytes. The role of oxygen sensor on immune cells, particularly on regulatory T cell (Treg) function, has not been fully elucidated. The purpose of our study was to evaluate the role of PHD2 in the regulation of Treg phenotype and function. We demonstrate herein that selective ablation of PHD2 expression in Treg (PHD2ΔTreg mice) leads to a spontaneous systemic inflammatory syndrome, as evidenced by weight loss, development of a rectal prolapse, splenomegaly, shortening of the colon, and elevated expression of IFN-γ in the mesenteric lymph nodes, intestine, and spleen. PHD2 deficiency in Tregs led to an increased number of activated CD4 conventional T cells expressing a Th1-like effector phenotype. Concomitantly, the expression of innate-type cytokines such as Il1b, Il12a, Il12b, and Tnfa was found to be elevated in peripheral (gut) tissues and spleen. PHD2ΔTreg mice also displayed an enhanced sensitivity to dextran sodium sulfate-induced colitis and toxoplasmosis, suggesting that PHD2-deficient Tregs did not efficiently control inflammatory response in vivo, particularly those characterized by IFN-γ production. Further analysis revealed that Treg dysregulation was largely prevented in PHD2-HIF2α (PHD2-HIF2αΔTreg mice), but not in PHD2-HIF1α (PHD2-HIF1αΔTreg mice) double KOs, suggesting an important and possibly selective role of the PHD2-HIF2α axis in the control of Treg function. Finally, the transcriptomic analysis of PHD2-deficient Tregs identified the STAT1 pathway as a target of the PHD2-HIF2α axis in regulatory T cell phenotype and in vivo function. KW - regulatory T cell KW - oxygen sensor KW - inflammation JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -