Superactivation of an immune response triggered by oligomerized T cell epitopes.
The peptides bound to class II major histocompatibility complex (MHC) molecules extend out both ends of the peptide binding groove. This structural feature provided the opportunity to design multivalent polypeptide chains that cross-link class II MHC molecules through multiple, repetitive MHC binding sites. By using recombinant techniques, polypeptide oligomers were constructed that consist of up to 32 copies of an HLA-DR1-restricted T cell epitope. The epitope HA306-318, derived from influenza virus hemagglutinin, was connected by 12- to 36-aa long spacer sequences. These oligomers were found to cross-link soluble HLA-DR1 molecules efficiently and, upon binding to the MHC molecules of a monocyte line, to trigger signal transduction indicated by the enhanced expression of some cell surface molecules. A particularly strong effect was evident in the T cell response. A hemagglutinin-specific T cell clone recognized these antigens at concentrations up to three to four orders of magnitude lower than that of the peptide or the hemagglutinin protein. Both signal transduction in the monocyte and the proliferative response of the T cell were affected greatly by the length of the oligomer (i.e., the number of repetitive units) and the distance of the epitopes within the oligomer (spacing). Thus, the formation of defined clusters of T cell receptor/MHC/peptide antigen complexes appears to be crucial for triggering the immune response and can be used to enhance the antigenicity of a peptide antigen by oligomerizing the epitope.
Rötzschke
O
O
Department of Molecular and Cellular Biology, Harvard University, 7 Divinity Avenue, Cambridge, MA 02138, USA.
Falk
K
K
Strominger
J L
JL
D001483:Base Sequence; D002460:Cell Line; D019281:Dimerization; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II; D011948:Receptors, Antigen, T-Cell