SPECIFICITY AND PROMISCUITY AMONG NATURALLY PROCESSED PEPTIDES BOUND TO HLA-DR ALLELES

Naturally processed peptides were acid extracted from immunoaffinity-p urified HLA-DR2, DR3, DR4, DR7, and DR8. Using the complementary techn iques of mass spectrometry and Edman microsequencing, >200 unique pept ide masses were identified from each allele, ranging from 1,200 to 4,0 00 daltons (10-34 residues in length), and a total of 201 peptide sequ ences were obtained. These peptides were derived from 66 different sou rce proteins and represented sets nested at both the amino- and carbox y-terminal ends with an average length of 15-18 amino acids. Strikingl y, most of the peptides (>85%) were derived from endogenous proteins t hat intersect the endocytic/class II pathway, even though class II mol ecules are thought to function mainly in the presentation of exogenous foreign peptide antigens. The predominant endogenous peptides were de rived from major histocompatibility complex-related molecules. A few p eptides derived from exogenous bovine serum proteins were also bound t o every allele. Four prominent promiscuous self-peptide sets (capable of binding to multiple HLA-DR alleles) as well as 84 allele-specific p eptide sets were identified. Binding experiments confirmed that the pr omiscuous peptides have high affinity for the binding groove of all HL A-DR alleles examined. A potential physiologic role for these endogeno us self-peptides as immunomodulators of the cellular immune response i s discussed.