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J. Biol. Chem., Vol. 279, Issue 43, 44243-44249, October 22, 2004

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Antibody Specific for the Peptide·Major Histocompatibility Complex

IS IT T CELL RECEPTOR-LIKE?^*

Tatiana Mareeva, Tatiana Lebedeva, Nadia Anikeeva, Tim Manser, and Yuri Sykulev

From the Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

Antibodies recognizing peptide bound to a major histocompatability 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-2K^b 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 V_H and V_L 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.

Received for publication, June 23, 2004 , and in revised form, July 21, 2004.

^* This work was supported by National Institutes of Health Research Grants AI43254 and AI39966 (to Y. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY704179 and AY704180.

To whom correspondence should be addressed: Dept. of Microbiology and Immunology, Kimmel Cancer Center, Bluemle Life Science Building 650, Thomas Jefferson University, Philadelphia, PA 19107. Tel.: 215-503-4530; Fax: 215-923-0249. E-mail: ysykulev{at}lac.jci.tju.edu.

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