Vaccination with DNA encoding a single-chain TCR fusion protein induces anticlonotypic immunity and protects against T-cell lymphoma.
The clonotypic T-cell antigen receptor (TCR) provides unique Valpha and Vbeta sequences with potential as idiotypic targets for immunoregulation. For T-cell malignancies, vaccination with the TCR could induce therapeutic anti-idiotypic responses. To facilitate this approach, we have developed DNA vaccines that include the genes encoding TCR sequences from a T-cell lymphoma (TCL). To combine requirements for stable folding with a simple minimized single-chain construction, we used a three-domain ValphaVbetaCbeta sequence. To promote anti-TCR immunity, we fused a pathogen-derived sequence from tetanus toxin to the 3'-end of the single-chain TCR. The fusion gene vaccine induced anti-idiotypic antibodies and generated protection against the TCL. The critical requirement for the conformational integrity of the delivered TCR antigen was highlighted by the observation that DNA fusion vaccines containing either ValphaVbeta or VbetaCbeta sequences failed to generate antibodies reactive with the native TCR or provide protection. This is the first report of a DNA vaccine able to induce anti-idiotypic immunity against TCL, and it presents a simple strategy for selectively eliminating T-cell clones in vivo.
Thirdborough
Stephen M
SM
Molecular Immunology Group, Tenovus Laboratory, Southampton University Hospitals Trust, Southampton SO16 6YD, United Kingdom.
Radcliffe
Joanna N
JN
Friedmann
Peter S
PS
Stevenson
Freda K
FK
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000096:biosynthesis* / Q000276:immunology; D000912:Antibodies, Neoplasm / Q000096:biosynthesis / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D007116:Immunization, Passive; D016399:Lymphoma, T-Cell / Q000276:immunology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics* / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013744:Tetanus Toxin / Q000235:genetics / Q000276:immunology; D019444:Vaccines, DNA / Q000235:genetics* / Q000276:immunology* / Q000627:therapeutic use; D014614:Vaccines, Synthetic / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use
D000888:Antibodies, Anti-Idiotypic; D000912:Antibodies, Neoplasm; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011993:Recombinant Fusion Proteins; D013744:Tetanus Toxin; D019444:Vaccines, DNA; D014614:Vaccines, Synthetic