Polymorphic proteins are often the targets of T and B lymphocytes in alloimmune responses. The polymorphic residue 33 of integrin beta3 is responsible for both a B cell response and a T cell response. Leu at position 33 controls the epitopes recognized by alloantibodies generated in individuals homozygous for Pro at 33. The alloantibody response shows a tight class II MHC restriction, and T cells have been identified that respond to the alloantigen. As part of the T cell response, the alloantigen could be recognized as foreign, and the autoantigen would be ignored due to self-tolerance. Alternatively, the polymorphism could change the ability of the peptide to bind. We tested these two possibilities using synthetic peptides corresponding to the polymorphic region and insect cell-derived class II MHC. The Leu33-containing peptide bound to the restricting MHC allele, whereas the Pro33 peptide did not. Thus, the presence of Leu at position 33 generates an anchor specific for the restricting MHC allele and helps define the peptide binding motif of this allele, HLA-DRB3*0101 (DR52a). These data indicate that certain alloresponses can be viewed entirely as foreign because the polymorphism generates a functional anchor residue in a peptide that otherwise would not bind. On the basis of these results, we would predict a unidirectional alloantibody response as the lack of binding of the Pro33 peptide would preclude T cell help. This could explain the observation that alloantibodies to the Pro33 allele are very rare.