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The Mode of Ligand Recognition by Two Peptide:MHC Class I-Specific Monoclonal Antibodies¹

Ilhem Messaoudi^*,, Joël LeMaoult^* and Janko Nikoli-ugi^2,*,

^* Laboratory of T Cell Development, Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021; and Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021

The Ig superfamily members TCR and B cell receptor (BCR) share high structural and amino acid homology, yet interact with Ags in a distinct manner. The overall shape of the TCR ligand is rather constant, with the variation coming from the MHC polymorphism and the peptide heterogeneity. Consequently, the TCR - and ß-chains form a relatively flat ligand-binding site that interacts with the peptide:MHC (pep:MHC) ligand in a fixed diagonal orientation relative to the MHC -helices, with the - and ß-chains of the TCR contacting the N and C termini of the pep:MHC complex, respectively. By contrast, the shape of BCR ligands varies dramatically, and the BCR exhibits much greater variability of the Ag-binding site. The mAbs 25-D1.16 (D1) and 22-C5.9 (C5), specific for the OVA-8:H-2K^b complex, allowed us to directly compare how TCR and BCR approach the same ligand. To that effect, we mapped D1 and C5 footprints over the OVA-8:H-2K^b complex. Using peptide variants and mutant MHC molecules, we show that the D1 and C5 contacts with the OVA-8:K^b complex C terminus overlap with the TCR ß-chain footprint, but that this footprint also extends to the regions of the molecule not contacted by the TCR. These studies suggest that D1 and C5 exhibit a hybrid mode of pep:MHC recognition, in part similar to that of the TCR ß-chain and in part similar to the conventional anti-MHC Ab.

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