A biological function for the XP motif within the N terminus of major histocompatibility complex class II-associated peptides.

A high proportion (up to 30%) of major histocompatibility complex (MHC) class II-bound peptides in the mouse and humans contains a proline residue at the N-terminal penultimate position (XP motif). We used a set of ovalbumin (OVA)-specific and hen egg lysozyme (HEL)-specific T cell hybridomas and asked whether the XP motif in MHC class II-associated peptides might influence the stimulation of T cells. We created N-terminally substituted variants of OVA323-339, an H2-Ad restricted OVA epitope and of HEL50-63, a dominant epitope in the context of H2-Ak. Our results show that the N-terminal sequence of MHC class II-bound peptides has a strong impact for the overall stimulation of specific T cells. Proline at the N terminus of antigenic peptides, in contrast to other amino acids, is tolerated or even enhances the recognition of MHC class II-bound peptides significantly.