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Back to the fold: T cell recognition of HFE, a MHC class Ib molecule that regulates iron metabolism
- Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892-0440
Hereditary hemochromatosis (HH), a disease resulting from iron overload, is the most common genetic disorder in the United States, afflicting more than a million Americans. Untreated, HH frequently leads to a middle-aged demise due to the failure of an iron-damaged liver, heart, or pancreas. Those whose ancestors hail from the regions of Europe where the Vikings left their genetic imprint (1) have a 1 in 10 chance of harboring the recessive mutation that is the most common cause of HH. HH was one of the first diseases linked to the major histocompatibility complex (MHC) (2). Inasmuch as the MHC typically encodes proteins like class I molecules that function to present peptides derived from intracellular pathogens to CD8 T cells (TCD8+), it would seem an unlikely locus for an iron metabolism gene. But nature typically works in mysterious ways, and this observation and a number of additional clues eventually led HH sleuths to HFE (3, 4), a gene product that is but one of a number of MHC “class Ib” molecules, molecules highly similar genetically and structurally to class I molecules but with myriad divergent functions. HH results from misfolding of HFE induced by a point mutation that replaces the normal cysteine residue at position 282 with a tyrosine. Despite clear genetic evidence that HFE causes HH in humans, and in mice with targeted deletions in HFE (5), it is unclear exactly how HFE influences iron metabolism (6). Although attention has focused on the known interaction of HFE with the transferrin receptor (7) and possible interactions with other iron-binding proteins, other lines of evidence point to contribution of the cellular immune system to HH (8). In this issue of PNAS, Rohrlich et al. (9) bring HFE back to the immune fold by clearly demonstrating that HFE can be recognized …
