In a recent clinical trial of immunosuppression withdrawal in adult liver transplant recipients, operational tolerance was associated with development of a transient lymphocyte infiltration rich in regulatory T cells (Treg). In addition, before the initiation of weaning, non-tolerant recipients exhibited lower serum ferritin and hepcidin levels than both tolerant patients and non-transplanted controls, despite having iron parameters within normal reference ranges. We thus investigated the potential influence of iron deficiency on Treg biology. Treg cells were induced in vitro from isolated murine naïve T cells employing plate-bound anti-CD3/CD28, IL-2 and TGFß alone or in the presence of low doses of the highly specific hydroxypyridinone iron chelator CP182 (5uM) or desferoxamine (DFO; 10uM). Iron chelation resulted in reduced cell proliferation and CD4+FOXP3+ Treg generation. The decreased number of CD4+FOXP3+ T cells was apparent even among undivided cells, suggesting a direct effect of iron deficiency on FOXP3+ expression. These changes were associated with a significant reduction of CD25 expression and STAT5 phosphorylation. The reduced CD25 expression, cell proliferation and Treg induction could all be reversed by addition of supplementary iron, but not by high-dose IL-2 (1,000 Units). Finally, iron chelation did not inhibit Treg generation if added to the in vitro culture 24 hours after T cell activation, suggesting an essential role of iron in the early steps of Treg differentiation. In short, iron deficiency impairs Treg induction, inhibiting T cell activation and subsequently cell proliferation. These results suggest iron deficiency could be detrimental in clinical situations where Treg induction is required, and provide additional information to the mechanisms responsible for the establishment of liver allograft tolerance.

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