The Journal of Experimental Medicine
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Published online 22 November 2004 doi:10.1084/jem.20040217
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 11, 1445-1454
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Structural Basis for the Restoration of TCR Recognition of an MHC Allelic Variant by Peptide Secondary Anchor Substitution

Michael J. Miley1, Ilhem Messaoudi3,4, Beatrix M. Metzner3,4, Yudong Wu1, Janko Nikolich-Zugich3,4, and Daved H. Fremont1,2

1 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110
2 Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110
3 Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006
4 Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006

Address correspondence to Daved H. Fremont, Dept. of Pathology and Immunology and Dept. of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110. Phone: (314) 747-6547; Fax: (314) 362-8888; email: fremont{at}pathbox.wustl.edu

Major histocompatibility complex (MHC) class I variants H-2Kb and H-2Kbm8 differ primarily in the B pocket of the peptide-binding groove, which serves to sequester the P2 secondary anchor residue. This polymorphism determines resistance to lethal herpes simplex virus (HSV-1) infection by modulating T cell responses to the immunodominant glycoprotein B498-505 epitope, HSV8. We studied the molecular basis of these effects and confirmed that T cell receptors raised against Kb–HSV8 cannot recognize H-2Kbm8–HSV8. However, substitution of SerP2 to GluP2 (peptide H2E) reversed T cell receptor (TCR) recognition; H-2Kbm8–H2E was recognized whereas H-2Kb–H2E was not. Insight into the structural basis of this discrimination was obtained by determining the crystal structures of all four MHC class I molecules in complex with bound peptide (pMHCs). Surprisingly, we find no concerted pMHC surface differences that can explain the differential TCR recognition. However, a correlation is apparent between the recognition data and the underlying peptide-binding groove chemistry of the B pocket, revealing that secondary anchor residues can profoundly affect TCR engagement through mechanisms distinct from the alteration of the resting state conformation of the pMHC surface.

Key Words: major histocompatibility complex • crystallography • antigen presentation • herpes simplex virus 1 • T cells

Abbreviations used in this paper: ASU, asymmetric unit; CD, circular dichroism; pMHC, MHC class I molecule in complex with bound peptide; SC, shape complementarity; Tm, midpoint of thermal denaturation.


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