Antibody specific for the peptide.major histocompatibility complex. Is it T cell receptor-like?
Antibodies recognizing peptide bound to a major histocompatibility complex (MHC) protein usually have a higher affinity for the composite peptide.MHC (pMHC) ligand than T cell receptors (TCR) with the same specificity. Because the solvent-accessible peptide area constitutes only a small portion of the contacting pMHC surface, we hypothesized that the contribution of the MHC moiety to the TCR-pMHC complex stability is limited, ensuring a small increment of the binding energy delivered by the peptide to be distinguishable by the TCR or the peptide-specific antibody. This suggests that the gain in affinity of the antibody-pMHC interaction can be achieved through an increase in the on-rate without a significant change in the off-rate of the interaction. To test the hypothesis, we have analyzed the binding of an ovalbumin peptide (pOV8) and its variants associated with soluble H-2Kb protein to the 25-D1.16 monoclonal antibody and compared it with the binding of the same pMHC complexes to the OT-1 TCR. This comparison revealed a substantially higher on-rate of the antibody-pMHC interaction compared with the TCR-pMHC interaction. In contrast, both the antibody and the TCR-pMHC complexes exhibited comparably fast off-rates. Sequencing of the 25-D1.16 VH and VL genes showed that they have very few somatic mutations and those occur mainly in framework regions. We propose that the above features constitute a signature of the recognition of MHC-bound peptide antigens by TCR and TCR-like antibodies, which could explain why the latter are rarely produced in vivo.
Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Tatiana
T
Mareeva
Tatiana
T
Lebedeva
Nadia
N
Anikeeva
Tim
T
Manser
Yuri
Y
Sykulev
D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000737:chemistry; D000911:Antibodies, Monoclonal / Q000737:chemistry; D000918:Antibody Specificity; D001483:Base Sequence; D015374:Biosensing Techniques; D003001:Cloning, Molecular; D004247:DNA / Q000737:chemistry; D004492:Edetic Acid / Q000737:chemistry; D006825:Hybridomas / Q000378:metabolism; D007128:Immunoglobulin Fragments; D007700:Kinetics; D008285:Major Histocompatibility Complex; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D010047:Ovalbumin / Q000737:chemistry; D010455:Peptides / Q000737:chemistry*; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D013816:Thermodynamics; D013997:Time Factors; D014162:Transfection
D000906:Antibodies; D000911:Antibodies, Monoclonal; D007128:Immunoglobulin Fragments; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D010047:Ovalbumin; D004247:DNA; D004492:Edetic Acid