Abstract
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.
Highlights
CD4+ regulatory T cells (Tregs), accounting for approximately 5-10% of total circulating CD4+ T cells, represent a critical subset of T lymphocytes involved in immune homeostasis
The present study highlights the important role of the prolyl-hydroxylase PHD2 in the regulation of Treg development and function
Deletion of PHD2 in developing, Tregs led to the accumulation of the subset of Treg precursor characterized by low expression of 370 Foxp[3], at the expenses of the mature, Foxp3+CD25+ Treg population (Figure 2c)
Summary
CD4+ regulatory T cells (Tregs), accounting for approximately 5-10% of total circulating CD4+ T cells, represent a critical subset of T lymphocytes involved in immune homeostasis. Uniformly characterized by the expression of the lineage-specific, Foxp[3] transcription 60 factor[1], regulatory T cells display a wide range of phenotypic and functional properties that allow them to migrate to specific sites and suppress a variety of immune reactions 62 including inflammatory[8] and humoral responses[9]. Short-range suppressive mechanisms include competition for nutrients and/or growth factors (mostly cytokines), secretion of immunosuppressive factors and direct, 66 contact-mediated, inactivation of antigen presenting cells[11].
Published Version
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