Subjugation of dominant immunogenic determinants within a chimeric peptide.

The mechanism of immunodominance was investigated using chimeric peptides from mouse myelin basic protein consisting of the immunodominant I-Au-restricted Ac1-11, attached by a peptide bond to I-Eu-restricted 35-47. Our results indicate that this chimeric peptide and certain of its derivatives were excellent immunogens both in vitro and in vivo. Notably, on immunization with Ac1-11:35-47 or Ac1-11 (Ala4):35-47, the proliferative T cell responses to each of its component peptides were almost completely "subjugated" in favor of neo-determinants that are I-Eu restricted. Furthermore, each of 11 hybridomas derived after immunization with Ac1-11:35-47 had specificity for junctional neo-determinants and none could be stimulated to produce interleukin-2 from Ac1-11 or 35-47. Subjugation of the immunogenicity of the original determinants occurred regardless of their dominance when separate. It did not appear to result from non-availability of the original determinants because the chimeric peptide was able to induce neonatal tolerance to each of its constituents. These results indicate that in an overlapping multideterminant array, the dominant determinant is unpredictable from historical data about any of the components. Determinant choice, at any stage of processing, may be governed by competitive aspects of determinant capture in an environment where all components--antigen, major histocompatibility complex and T cell receptor--are available.