CLASS I molecules of the major histocompatibility complex (MHC) transport peptides to the cell surface for surveillance by T cells1. Ligand specificity is stringent and differs from allele to allele2-4. Here we report analysis of natural ligands of 'unconventional' glycophosphatidyl- anchored mouse class I molecules, Qa-2. The function of these molecules is unclear5-6; they can serve as recognition structures for 'unrestricted' cytotoxic T cells but have not been found to present peptides to T cells, although the DNA sequence suggests a similar peptide binding groove to that of 'conventional' class I molecules7, and other unconventional class I molecules can present antigens in a few cases8-10. Pool sequencing of natural Qa-2 ligands shows that Qa-2 molecules are indeed peptide receptors, having ligand specificity similar to that of conventional class I molecules, that is, a predominant length of nine amino acids, anchor positions, and hydrophobic termination of peptides. But ligand specificity is much more stringent than with other class I molecules: of the nine positions, two are anchors and four have rather limited occupancy.
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