| First Author | Ajouaou Y | Year | 2022 |
| Journal | Elife | Volume | 11 |
| PubMed ID | 35192456 | Mgi Jnum | J:321651 |
| Mgi Id | MGI:6887186 | Doi | 10.7554/eLife.70555 |
| Citation | Ajouaou Y, et al. (2022) The oxygen sensor prolyl hydroxylase domain 2 regulates the in vivo suppressive capacity of regulatory T cells. Elife 11:e70555 |
| abstractText | The oxygen sensor prolyl hydroxylase domain 2 (PHD2) plays an important role in cell hypoxia adaptation by regulating the stability of HIF proteins (HIF1alpha and HIF2alpha) 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 (PHD2(DeltaTreg) 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-gamma 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. PHD2(DeltaTreg) 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-gamma production. Further analysis revealed that Treg dysregulation was largely prevented in PHD2-HIF2alpha (PHD2-HIF2alpha(DeltaTreg) mice), but not in PHD2-HIF1alpha (PHD2-HIF1alpha(DeltaTreg) mice) double KOs, suggesting an important and possibly selective role of the PHD2-HIF2alpha 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-HIF2alpha axis in regulatory T cell phenotype and in vivo function. |
