Immunodominance: intermolecular competition between MHC class II molecules by covalently linked T cell epitopes.
The T cell response to complex protein Ag typically focuses on a few, and frequently a single, immunodominant epitope. Several groups have proposed that the mechanism of immunodominance is determined by the steps of Ag processing and presentation including protein unfolding, the sites of proteolytic cleavage, and the affinity of binding to MHC molecules. Also, the failure of the TCR repertoire to recognize MHC-bound peptides, termed a hole in the repertoire, can prevent recognition of a potentially dominant processed peptide. In the present study, we demonstrate that immunodominance can be determined by intermolecular competition for binding to MHC class II molecules between covalently linked T cell epitopes. In addition, we have analyzed the factors controlling T cell recognition of the covalently linked epitopes. In our system, T cell recognition of the dominant epitope is not altered by Ag processing, and is not simply a function of MHC-binding affinity. We propose that adjacent sequences can subtly alter the conformation of an epitope, creating significant changes in T cell recognition. These observations are discussed in terms of the mechanisms of immunodominance and in terms of the development of synthetic peptide vaccines.
Wang
Y
Y
Laboratory of Immunogenetics and Transplantation, Brigham and Women's Hospital, Boston, MA 02115.
Smith
J A
JA
Gefter
M L
ML
Perkins
D L
DL
D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006825:Hybridomas / Q000276:immunology; D016056:Immunodominant Epitopes / Q000276:immunology*; D051379:Mice; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D000949:Histocompatibility Antigens Class II; D016056:Immunodominant Epitopes; D010446:Peptide Fragments