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* Institut de Biologie Structurale Jean-Pierre Ebel, Unité mixte de recherche 5075 (CEA, CNRS, UJF, PSB), Grenoble, France;
INSERM, Unité 892, Institut de Recherche Thérapeutique, Université de Nantes, Nantes, France; and
Centre d'Immunologie de Marseille-Luminy, Université de la Méditerrannée, INSERM, Unité 631, CNRS, Marseille, France
Protective T cell responses elicited along chronic human CMV (HCMV) infections are sometimes dominated by CD8 T cell clones bearing highly related or identical public TCR in unrelated individuals. To understand the principles that guide emergence of these public T cell responses, we have performed structural, biophysical, and functional analyses of an immunodominant public TCR (RA14) directed against a major HLA-A*0201-restricted HCMV Ag (pp65495–503) and selected in vivo from a diverse repertoire after chronic stimulations. Unlike the two immunodominant public TCRs crystallized so far, which focused on one peptide hotspot, the HCMV-specific RA14 TCR interacts with the full array of available peptide residues. The conservation of some peptide-MHC complex-contacting amino acids by lower-affinity TCRs suggests a shared TCR-peptide-MHC complex docking mode and supports an Ag-driven selection of optimal TCRs. Therefore, the emergence of a public TCR of an oligoclonal Ag-specific response after repeated viral stimulations is based on a receptor displaying a high structural complementarity with the entire peptide and focusing on three peptide hotspots. This highlights key parameters underlying the selection of a protective T cell response against HCMV infection, which remains a major health issue in patients undergoing bone marrow transplantation.
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 study was supported in part by the Agence Nationale de la Recherche (Grant ANR-05-MIIM-019). B.M. and M.B. were also supported by the EPI-PEPVAC European Union Grant. The authors have declared that no competing interests exist.
2 S.G. and X.S. equally contributed to the work.
3 Current address: The Protein Crystallography Unit, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia.
4 Current address: Infection and Immunity Division, Centre for Cancer Research and Cell Biology, School of Biomedical Sciences, Queens University, Belfast, Northern Ireland.
5 Address correspondence and reprint requests to Dr. Marc Bonneville, INSERM, Unité 892, Institut de Recherche Thérapeutique, 9 quai Moncousu, Université de Nantes, F-44035 Nantes, France. E-mail address: bonnevil{at}nantes.inserm.fr, or Dominique Housset, Institut de Biologie Structurale Jean-Pierre Ebel, Unité mixte de recherche 5075 (CEA, CNRS, UJF, PSB), 41 rue Jules Horowitz, F-38027 Grenoble, France. E-mail address: dominique.housset{at}ibs.fr
6 Abbreviations used in this paper: HCMV, human CMV; A2, HLA-A*0201 allele; FLR, FLRGRAYGL; NLV, NLVPMVATV; PEG, polyethylene glycol; pMHC, peptide-MHC; pMHCI, pMHC class I; RA14-NLV-A2, RA14 TCR-NLV-A2 complex; SPR, surface plasmon resonance; TAP, transporter associated with Ag processing.
7 The online version of this article contains supplemental material.
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