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 (IEL) expressing the gamma/delta (γδ) T-cell receptor (TCR), suggested a potential role of 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[sup-/-]) mice followed by the TCR-δ knockout (TCR&delta[sup-/-] animals. TCR-α knockout (TCR&alpha[sup-/-] 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)-&alpha 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-&alpha 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. [ABSTRACT FROM AUTHOR]