Allele-specific variation in the degeneracy of major histocompatibility complex (MHC) restriction

The role of peptides in determining immune responses for both allorecognition and antigen-specific recognition has been clearly documented. The importance of different regions of the major histocompatibility complex (MHC) class II molecule in contributing to recognition has been demonstrated by studies involving site-directed mutagenesis and exon shuffling. These studies have indicated that the N-terminal region of the MHC class II molecule has a role to play in contributing to the T-cell receptor (TCR)-MHC-peptide interaction. Variation in the importance of different regions of the MHC class II molecule may be dependent on different aspects of this interaction, such as restriction specificity and affinity of the responding T-cell clone, and the nature of the bound peptide. We demonstrate here that the degree of T-cell degeneracy may be allele dependent. Thus, a series of exon-shuffled molecules were generated by shuffling the first and second variable region of a particular DR beta 1 molecule with the third variable region of a different DR beta 1 molecule. A panel of transfectants, which expressed these hybrid molecules, was then generated and used as antigen-presenting cells (APCs). A panel of peptide-specific T-cell clones was generated using the native HLA-DR molecules as the restricting elements. For the majority of restricting alleles, HLA-DRB5*0101, HLA-DRB1*1101, and HLA-DRB1*0701, all three variable regions were required for recognition. The exception to this observation was HLA-DRB1*0401, which was degenerate. Such degeneracy may facilitate the breakdown of self-tolerance through the cross-reactive recognition of other alleles in DR4/DR"x" heterozygotes. Such an observation as this may contribute to our understanding of the etiopathology of rheumatoid arthritis, an autoimmune disease strongly associated with HLA-DRB1*0401.