γδ intraepithelial lymphocytes drive tumor necrosis factor-α responsiveness to intestinal iron challenge: Relevance to hemochromatosis

The dependence of intestinal epithelial cell (IEC) growth and differentiation on intraepithelial lymphocytes (IELs) expressing the gamma/delta (γδ) T-cell receptor (TCR), suggested a potential role for γδ⁺ IELs in the regulation of iron absorption. We therefore examined the levels of hepatic iron and the IEL cytokine responses in C57BL/6J control and class I and TCR knockout lines (placed on a C57BL/6J genetic background) following the administration of supplemental dietary iron. The highest level of liver iron was found in the β2-microglobulin knockout (β2m(-/-)) mice followed by the TCR-δ knockout (TCRδ(-/-)) animals. TCR-α knockout (TCRα(-/-)) and control animals did not differ in their iron levels. Liver iron loading correlated inversely with the ability of the mice to generate an IEL tumor necrosis factor (TNF)-α response. These observations suggest a model in which IEC iron loading is communicated to IELs via the HFE class I protein. The result of this communication is the initiation of TNF-α release by γδ⁺ IELs (sustained by macrophages and dendritic cells) contributing to the upregulation of ferritin expression and possibly to the normal maintenance of the IEC apoptotic pathway.