Human Cytomegalovirus Epitope Dominant Selection of a Public TCR against a Structural Bases for the Affinity-Driven

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 (pp65 495–503 ) 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 Journal of Immunology, 2009, 183: 430–437.

[1]  Philippa Marrack,et al.  Evolutionarily conserved amino acids that control TCR-MHC interaction. , 2008, Annual review of immunology.

[2]  D. Price,et al.  The molecular basis for public T-cell responses? , 2008, Nature Reviews Immunology.

[3]  J. McCluskey,et al.  T-cell receptor bias and immunity. , 2008, Current opinion in immunology.

[4]  Marc Bonneville,et al.  Kinetic evidence for a ligand-binding-induced conformational transition in the T cell receptor , 2007, Proceedings of the National Academy of Sciences.

[5]  Jennifer Maynard,et al.  Structural evidence for a germline-encoded T cell receptor–major histocompatibility complex interaction 'codon' , 2007, Nature Immunology.

[6]  Nicholas A Williamson,et al.  A T cell receptor flattens a bulged antigenic peptide presented by a major histocompatibility complex class I molecule , 2007, Nature Immunology.

[7]  P. Doherty,et al.  Structural determinants of T-cell receptor bias in immunity , 2006, Nature Reviews Immunology.

[8]  M. Bonneville,et al.  Impact of CD8-MHC class I interaction in detection and sorting efficiencies of antigen-specific T cells using MHC class I/peptide multimers: contribution of pMHC valency. , 2006, International immunology.

[9]  Robyn L Stanfield,et al.  How TCRs bind MHCs, peptides, and coreceptors. , 2006, Annual review of immunology.

[10]  M. Bonneville,et al.  Selection of T Cell Clones Expressing High-Affinity Public TCRs within Human Cytomegalovirus-Specific CD8 T Cell Responses1 , 2005, The Journal of Immunology.

[11]  Natalie A Borg,et al.  T cell receptor recognition of a 'super-bulged' major histocompatibility complex class I–bound peptide , 2005, Nature Immunology.

[12]  Andrew Sewell,et al.  Structural and kinetic basis for heightened immunogenicity of T cell vaccines , 2005, The Journal of experimental medicine.

[13]  Kevin Cowtan,et al.  research papers Acta Crystallographica Section D Biological , 2005 .

[14]  David I Stuart,et al.  A structural basis for immunodominant human T cell receptor recognition , 2003, Nature Immunology.

[15]  P. Moss,et al.  Comparative analysis of CD8+ T cell responses against human cytomegalovirus proteins pp65 and immediate early 1 shows similarities in precursor frequency, oligoclonality, and phenotype. , 2002, The Journal of infectious diseases.

[16]  M. Wills,et al.  Latency and reactivation of human cytomegalovirus. , 2002, The Journal of infection.

[17]  P. Coulie,et al.  High-resolution structure of HLA-A*0201 in complex with a tumour-specific antigenic peptide encoded by the MAGE-A4 gene. , 2001, Journal of molecular biology.

[18]  D. Wiley,et al.  Structure of a covalently stabilized complex of a human αβ T‐cell receptor, influenza HA peptide and MHC class II molecule, HLA‐DR1 , 2000, The EMBO journal.

[19]  M. Bonneville,et al.  A global appraisal of immunodominant CD8 T cell responses to Epstein‐Barr virus and cytomegalovirus by bulk screening , 2000, European journal of immunology.

[20]  C. Tournay,et al.  Characterization of CMVpp65-specific CD8+ T lymphocytes using MHC tetramers in kidney transplant patients and healthy participants. , 2000, Transplantation.

[21]  C. Tournay,et al.  Efficient detection and immunomagnetic sorting of specific T cells using multimers of MHC class I and peptide with reduced CD8 binding , 2000, Nature Medicine.

[22]  H. Rammensee,et al.  SYFPEITHI: database for MHC ligands and peptide motifs , 1999, Immunogenetics.

[23]  J. Schneider-Mergener,et al.  Target Structures of the CD8+-T-Cell Response to Human Cytomegalovirus: the 72-Kilodalton Major Immediate-Early Protein Revisited , 1999, Journal of Virology.

[24]  M. Weekes,et al.  The Memory Cytotoxic T-Lymphocyte (CTL) Response to Human Cytomegalovirus Infection Contains Individual Peptide-Specific CTL Clones That Have Undergone Extensive Expansion In Vivo , 1999, Journal of Virology.

[25]  J. York,et al.  Development of a candidate HLA A*0201 restricted peptide-based vaccine against human cytomegalovirus infection. , 1997, Blood.

[26]  X. Jin,et al.  The human cytotoxic T-lymphocyte (CTL) response to cytomegalovirus is dominated by structural protein pp65: frequency, specificity, and T-cell receptor usage of pp65-specific CTL , 1996, Journal of virology.

[27]  S. L. Silins,et al.  T cell receptor repertoire for a viral epitope in humans is diversified by tolerance to a background major histocompatibility complex antigen , 1995, The Journal of experimental medicine.

[28]  J. Bell,et al.  Human HLA-A0201-restricted cytotoxic T lymphocyte recognition of influenza A is dominated by T cells bearing the V beta 17 gene segment , 1995, The Journal of experimental medicine.

[29]  D J Moss,et al.  Dominant selection of an invariant T cell antigen receptor in response to persistent infection by Epstein-Barr virus , 1994, The Journal of experimental medicine.

[30]  S. Riddell,et al.  Identification of the major late human cytomegalovirus matrix protein pp65 as a target antigen for CD8+ virus‐specific cytotoxic T lymphocytes , 1994, Journal of medical virology.

[31]  J. Navaza,et al.  AMoRe: an automated package for molecular replacement , 1994 .

[32]  Wolfgang Kabsch,et al.  Automatic processing of rotation diffraction data from crystals of initially unknown symmetry and cell constants , 1993 .

[33]  D. Wiley,et al.  HLA-A2-peptide complexes: refolding and crystallization of molecules expressed in Escherichia coli and complexed with single antigenic peptides. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[34]  J. Bell,et al.  Extensive conservation of alpha and beta chains of the human T-cell antigen receptor recognizing HLA-A2 and influenza A matrix peptide. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[35]  J. Zou,et al.  Improved methods for building protein models in electron density maps and the location of errors in these models. , 1991, Acta crystallographica. Section A, Foundations of crystallography.

[36]  J. Sissons,et al.  Human cytomegalovirus-specific cytotoxic T cells. Relative frequency of stage-specific CTL recognizing the 72-kD immediate early protein and glycoprotein B expressed by recombinant vaccinia viruses , 1988, The Journal of experimental medicine.

[37]  J. Manischewitz,et al.  HLA-restricted cytotoxic T lymphocytes are an early immune response and important defense mechanism in cytomegalovirus infections. , 1984, Reviews of infectious diseases.

[38]  J. Whisstock,et al.  A Structural Basis for the Selection of Dominant αβ T Cell Receptors in Antiviral Immunity , 2003 .

[39]  P. Moss,et al.  Characterization of human cytomegalovirus peptide-specific CD8(+) T-cell repertoire diversity following in vitro restimulation by antigen-pulsed dendritic cells. , 2002, Blood.

[40]  Marie-Paule Lefranc,et al.  IMGT, the international ImMunoGeneTics database , 1999, Nucleic Acids Res..

[41]  L. Lally.  The CCP 4 Suite — Computer programs for protein crystallography , 1998 .