IMMUNODOMINANCE - A SINGLE AMINO-ACID SUBSTITUTION WITHIN AN ANTIGENIC SITE ALTERS INTRAMOLECULAR SELECTION OF T-CELL DETERMINANTS

The mechanism of immunodominance was studied by mutating a single amin o acid residue within an immunodominant determinant of Staphylococcus aureus nuclease (Nase). Residues 81 to 100, which can be further reduc ed to 86 to 100, were determined to be the immunodominant determinant of Nase in H-2k mice. By introducing selected single amino acid substi tutions into the peptide encompassing residues 86 to 100 (p86-100), re sidue 90 was shown to be one of the critical amino acids for T cell re cognition, inasmuch as most of the T cells recognizing p86-100 do not respond to a p86-100 analog with a substitution of leucine for ala nin e at the residue 90. A mutant of Nase with a replacement of alanine by leucine at residue 90 (A90L) was constructed, and for A90L region 112 to 130, which is a subdominant determinant in Nase, becomes immunodom inant. Although unable to respond to Nase, T cells primed in vivo with the peptides covering various cryptic determinants proliferate when c hallenged with A90L in vitro. Our results suggest that at the protein level there is competition among potential T cell determinants of prot ein Ag for binding to MHC molecules, and that this competition plays a role in determining which determinant may become immunodominant.