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.
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6 December 2004
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November 22 2004
Structural Basis for the Restoration of TCR Recognition of an MHC Allelic Variant by Peptide Secondary Anchor Substitution
Michael J. Miley,
Michael J. Miley
1Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110
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Ilhem Messaoudi,
Ilhem Messaoudi
3Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006
4Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006
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Beatrix M. Metzner,
Beatrix M. Metzner
3Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006
4Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006
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Yudong Wu,
Yudong Wu
1Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110
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Janko Nikolich-Žugich,
Janko Nikolich-Žugich
3Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006
4Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006
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Daved H. Fremont
Daved H. Fremont
1Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110
2Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110
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Michael J. Miley
1Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110
Ilhem Messaoudi
3Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006
4Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006
Beatrix M. Metzner
3Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006
4Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006
Yudong Wu
1Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110
Janko Nikolich-Žugich
3Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006
4Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006
Daved H. Fremont
1Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110
2Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110
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: [email protected]
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.
Received:
February 03 2004
Accepted:
October 25 2004
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2004
J Exp Med (2004) 200 (11): 1445–1454.
Article history
Received:
February 03 2004
Accepted:
October 25 2004
Citation
Michael J. Miley, Ilhem Messaoudi, Beatrix M. Metzner, Yudong Wu, Janko Nikolich-Žugich, Daved H. Fremont; Structural Basis for the Restoration of TCR Recognition of an MHC Allelic Variant by Peptide Secondary Anchor Substitution . J Exp Med 6 December 2004; 200 (11): 1445–1454. doi: https://doi.org/10.1084/jem.20040217
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