Engineered immunoglobulin molecules as vehicles for T cell epitopes.
The variable regions (V) of immunoglobulins (Ig) bear antigenic determinants that can stimulate both humoral and cellular immune responses subsequent to hetero, allo or iso-immunization. The expression of these determinants by Igs usually correlates with the presence of specific amino acid residues within the CDR loops of the V regions. Since the CDR loops varies in length, we reasoned that they would represent permissive sites to insert foreign peptides and create antigenized Igs expressing selected determinants. Taking advantage of these properties and the fact that Igs are self and long-lived molecules, we expressed a CTL and a helper epitope of influenza virus nucleoprotein and hemagglutinin respectively, within the heavy chain CDR3 loop of an anti-arsonate antibody. We found that foreign peptides comprised of 11 to 15 amino acid residues can be expressed within the V region of the heavy chain without alteration of pairing with the light chain. More striking, the cellular processing machinery is able to generate the peptides from the Ig context which were then recognized by specific T cells. Furthermore, the engineered Igs are able to induce T cell responses specific for the inserted peptide and for influenza virus. The use of engineered Ig molecules as vehicles for T and B cell peptides might represent a valuable strategy to generate safe, long lived reagents able to stimulate strong specific immune responses. This would then overcome the short half life of synthetic peptides based vaccines and the side effects seen in case of recombinant viral proteins or inactivated viruses based vaccines.
Zaghouani
H
H
Department of Microbiology, Mount Sinai School of Medicine, New York, New York 10029.
Kuzo
Y
Y
Kuzo
H
H
Mann
N
N
Daian
C
C
Bona
C
C
D000818:Animals; D000914:Antibodies, Viral / Q000235:genetics / Q000276:immunology; D000939:Epitopes / Q000235:genetics* / Q000276:immunology; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D006389:Hemagglutinins, Viral / Q000235:genetics / Q000276:immunology; D007136:Immunoglobulins / Q000235:genetics* / Q000276:immunology; D009980:Influenza A virus / Q000276:immunology; D019590:Nucleocapsid Proteins; D009698:Nucleoproteins / Q000235:genetics / Q000276:immunology; D014677:Pharmaceutical Vehicles; D015202:Protein Engineering; D016601:RNA-Binding Proteins; D013601:T-Lymphocytes / Q000276:immunology*; D014758:Viral Core Proteins / Q000235:genetics / Q000276:immunology
D000914:Antibodies, Viral; D000939:Epitopes; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D006389:Hemagglutinins, Viral; D007136:Immunoglobulins; C048842:NP protein, Influenza A virus; D019590:Nucleocapsid Proteins; D009698:Nucleoproteins; D014677:Pharmaceutical Vehicles; D016601:RNA-Binding Proteins; D014758:Viral Core Proteins