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Distinct CDR3 Conformations in TCRs Determine the Level of Cross-Reactivity for Diverse Antigens, but Not the Docking Orientation¹

Lindsay L. Jones^*, Leremy A. Colf, Jennifer D. Stone^*, K. Christopher Garcia^, and David M. Kranz^2,*

^* Department of Biochemistry, University of Illinois, Urbana, IL 61801; Department of Molecular and Cellular Physiology and Department of Structural Biology, Stanford University, Stanford, CA 94305; and Howard Hughes Medical Institute, Chevy Chase, MD 20815

T cells are known to cross-react with diverse peptide MHC Ags through their β TCR. To explore the basis of such cross-reactivity, we examined the 2C TCR that recognizes two structurally distinct ligands, SIY-K^b and alloantigen QL9-L^d. In this study we characterized the cross-reactivity of several high-affinity 2C TCR variants that contained mutations only in the CDR3 loop. Two of the TCR lost their ability to cross-react with the reciprocal ligand (SIY-K^b), whereas another TCR (m67) maintained reactivity with both ligands. Crystal structures of four of the TCRs in complex with QL9-L^d showed that CDR1, CDR2, and CDR3β conformations and docking orientations were remarkably similar. Although the CDR3 loop of TCR m67 conferred a 2000-fold higher affinity for SIY-K^b, the TCR maintained the same docking angle on QL9-L^d as the 2C TCR. Thus, CDR3 dictated the affinity and level of cross-reactivity, yet it did so without affecting the conserved docking orientation.

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.

¹ This work was supported by National Institutes of Health Grants GM55767 (to D.M.K.) and AI48540 (to K.C.G.), a predoctoral grant from the National Science Foundation (to L.A.C.), and the Samuel and Ruth Engelberg/Irvington Institute Fellowship of the Cancer Research Institute (to J.D.S.).

² Address correspondence and reprint requests to Dr. David M. Kranz, Department of Biochemistry, University of Illinois, 600 South Mathews Avenue, Urbana, IL 61801. E-mail address: d-kranz{at}uiuc.edu

³ Abbreviations used in this paper: pMHC, peptide MHC; sc, single chain; SPR, surface plasmon resonance; PDB, Brookhaven Protein Data Bank.

⁴ The online version of this article contains supplemental material.

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