Iron overload in HFE-related hemochromatosis severely impairs Vδ2+ γδ T-cell homeostasis

作者：Derya Erdoğdu, Ina Becoku, V. Huber, Yao Wang, Matthias K. Eyrich, Hisayoshi Hashimoto, Michaela Döring, Johannes Hubertus Schulte, Karin Schilbach · 发表于：Blood · 年份：2025 · DOI：10.1182/blood.2024025345 · 被引用次数：7 · 研究领域：Iron Metabolism and Disorders、Hemoglobinopathies and Related Disorders、Erythrocyte Function and Pathophysiology

ABSTRACT: HFE-related hemochromatosis induces systemic iron overload. Although extensive studies indicate a pivotal role for iron homeostasis in αβ T-cell immunity, its effect on γδ T cells is unknown. Here, we found a reversal of the Vδ2+/Vδ2- ratio in the γδ T-cell compartment as a feature of hemochromatosis, which is associated with a Vδ2+ population that cannot be enriched by zoledronic acid (ZOL) stimulation, despite evidence of T-cell receptor (TCR)-ligand formation and strong proliferative behavior. In vivo, reactive oxygen species (ROS) production and exhaustion marker expression are significantly increased on Vδ2+ T cells in hemochromatosis compared with healthy individuals. Ex vivo, hemochromatosis donor-derived Vδ2+ cells are hyporesponsive to TCR stimulation in terms of ROS production but significantly increase their paramount expression of exhaustion markers. Fas-Fas ligand coexpression indicates their high susceptibility to activation-induced cell death. Consistent therewith, FeSO4 alone induces Vδ2+ subset-specific proliferation in healthy peripheral blood mononuclear cells comparable to stimulation by ZOL, and blocking experiments identify FeSO4-induced proliferation as BTN3A1/TCR mediated. Pyrophosphate is key for Vδ2+-TCR ligand formation. Iron, by suppressing pyrophosphatase alkaline phosphatase, promotes their stability. Therefore, our data suggest that the transcriptional repression of pyrophosphatases, as under the conditions of iron overload in hemochro...