DIFFERENCES IN PEPTIDE BINDING OF DR11 AND DR13 MICROVARIANTS DEMONSTRATE THE POWER OF MINOR VARIATION IN GENERATING DR FUNCTIONAL DIVERSITY

The influence of subtle HLA diversification on antigen binding was exp lored using murine L-cell transfectants expressing alleles in the DR11 /DR13 family and a panel of peptides. The levels of binding among this family of DR microvariants were as diverse as the levels of binding a mong distantly related DR molecules. Even a single amino acid differen ce between allelic products had a profound effect on peptide binding. Specific amino acid substitutions, generated using site-directed mutag enesis to alter polymorphic residues at DR beta 32,37,57,58,67,71,86, demonstrated that a specific change within the context of a single DR molecule differed in its effect on the binding of specific peptides. I n addition, a specific amino acid substitution had a differential effe ct on the binding level of a peptide to different DR molecules. Each p olymorphic amino acid appeared to play a role in the binding of some p eptide. Studies using the aminoterminal portion of the invariant chain CLIP peptide suggested that this peptide may offer varying degrees of competition in the binding of the cellular peptide pool in cells expr essing different DR molecules. Finally, the results obtained with two strain-specific peptides from an immunodominant region of a malarial p arasite show differential binding to two DR13 molecules, suggesting th at immune pressure may promote parasite diversity. A dynamic interacti on may exist between pathogens and the immune system shaping the HLA p rofile in a population. Thus even subtle diversification of the HLA mo lecules, possibly pathogen driven, can have a substantial effect on pe ptide binding and immune recognition.