Gamma delta intraepithelial lymphocytes drive tumor necrosis factor-alpha 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 (gamma delta) T-cell receptor (TCR), suggested a potential role for gamma delta + 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 beta 2-microglobulin knockout (beta 2m-/-) mice followed by the TCR-delta knockout (TCR delta-/-) animals. TCR-alpha knockout (TCR alpha-/-) 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 gamma delta + 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.
D000595:Amino Acid Sequence; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D006680:HLA Antigens / Q000096:biosynthesis / Q000502:physiology; D006432:Hemochromatosis / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000502:physiology; D006801:Humans; D007408:Intestinal Absorption / Q000276:immunology; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D007501:Iron / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D008969:Molecular Sequence Data; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000502:physiology*; D013154:Spleen / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*