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.