Major histocompatibility complex class I allele‐specific peptide libraries: Identification of peptides that mimic an H‐Y T cell epitope

We describe a novel method for screening large libraries of random peptides for T cell antigens. Two libraries were constructed, containing fixed amino acids representing the major histocompatibility complex (MHC) class I anchor residues for H‐2K^b‐restricted octamers and H‐2D^b‐restricted nonamers. Peptides from the K^b‐restricted library (K^bL: SXIXFXXL) and the D^b‐restricted library (D^bL: XXXXNXXX^I_M) specifically stabilize empty K^b and D^b molecules, respectively. The libraries contain peptides that mimic several H‐2^b‐restricted cytotoxic T lymphocyte epitopes, and 21 mimotopes for a D^b‐restricted H‐Y epitope were isolated. A degenerate synthetic peptide of limited complexity containing the identified H‐Y sequence motif was found to be similar to the natural H‐Y epitope by reverse‐phase high performance liquid chromatography analysis. This peptide is also capable of immunizing female mice against male splenocytes. Several applications for MHC‐restricted peptide libraries are discussed.