A naturally processed peptide presented by HLA-A*0201 is expressed at low abundance and recognized by an alloreactive...

In contrast to T cells that respond to peptides presented by self MHC molecules, alloreactive T cells recognize determinants expressed on nonself MHC molecules. Because current positive selection models suggest that T cell affinity toward a nonself MHC molecule would be lower than that toward a self MHC molecule, we previously proposed that vigorous alloreactive responses would be generated preferentially toward those antigenic peptide complexes presented at the highest density on the cell surface. The high abundance of two class I MHC-associated peptides that have been identified as allo- or xenoantigens is consistent with this hypothesis. We report here the identification of a naturally processed peptide YLDPAQQNL that is presented by HLA-A*0201 and recognized by an alloreactive T cell clone. This peptide appears to originate from an unknown member of the zinc finger proteins. Quantitation by mass spectrometry indicates that this peptide is present on the surface at 85 to 125 copies per cell, comparable with the density of several other epitopes presented by HLA-A*0201 to self MHC-restricted T cells. In addition, based on the affinity of the peptide for HLA-A*0201 and the half-maximal peptide concentration required for T cell sensitization, this alloreactive T cell appears to have an affinity similar to or higher than that of many self MHC-restricted T cells. These data suggest that allogeneic responses can be directed against antigenic determinants of low abundance and that recognition of alloreactive peptides is not limited by a lower affinity of T cells for nonself MHC molecules.