Structural bases for the affinity-driven selection of a public TCR against a dominant human cytomegalovirus epitope

Stephanie Gras, Xavier Saulquin, Jean-Baptiste Reiser, Emilie Debeaupuis, Klara Echasserieau, Adrien Kissenpfennig, Francois Legoux, Anne Chouquet, Madalen Le Gorrec, Paul Machillot, Berangere Neveu, Nicole M Thielens, Bernard Malissen, Marc Bonneville, Dominique Housset

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Abstract

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.
Original languageEnglish
Pages (from-to)430 - 437
Number of pages8
JournalJournal of Immunology
Volume183
Issue number1
DOIs
Publication statusPublished - 2009

Cite this

Gras, S., Saulquin, X., Reiser, J-B., Debeaupuis, E., Echasserieau, K., Kissenpfennig, A., ... Housset, D. (2009). Structural bases for the affinity-driven selection of a public TCR against a dominant human cytomegalovirus epitope. Journal of Immunology, 183(1), 430 - 437. https://doi.org/10.4049/?jimmunol.0900556
Gras, Stephanie ; Saulquin, Xavier ; Reiser, Jean-Baptiste ; Debeaupuis, Emilie ; Echasserieau, Klara ; Kissenpfennig, Adrien ; Legoux, Francois ; Chouquet, Anne ; Le Gorrec, Madalen ; Machillot, Paul ; Neveu, Berangere ; Thielens, Nicole M ; Malissen, Bernard ; Bonneville, Marc ; Housset, Dominique. / Structural bases for the affinity-driven selection of a public TCR against a dominant human cytomegalovirus epitope. In: Journal of Immunology. 2009 ; Vol. 183, No. 1. pp. 430 - 437.
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abstract = "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.",
author = "Stephanie Gras and Xavier Saulquin and Jean-Baptiste Reiser and Emilie Debeaupuis and Klara Echasserieau and Adrien Kissenpfennig and Francois Legoux and Anne Chouquet and {Le Gorrec}, Madalen and Paul Machillot and Berangere Neveu and Thielens, {Nicole M} and Bernard Malissen and Marc Bonneville and Dominique Housset",
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Gras, S, Saulquin, X, Reiser, J-B, Debeaupuis, E, Echasserieau, K, Kissenpfennig, A, Legoux, F, Chouquet, A, Le Gorrec, M, Machillot, P, Neveu, B, Thielens, NM, Malissen, B, Bonneville, M & Housset, D 2009, 'Structural bases for the affinity-driven selection of a public TCR against a dominant human cytomegalovirus epitope', Journal of Immunology, vol. 183, no. 1, pp. 430 - 437. https://doi.org/10.4049/?jimmunol.0900556

Structural bases for the affinity-driven selection of a public TCR against a dominant human cytomegalovirus epitope. / Gras, Stephanie; Saulquin, Xavier; Reiser, Jean-Baptiste; Debeaupuis, Emilie; Echasserieau, Klara; Kissenpfennig, Adrien; Legoux, Francois; Chouquet, Anne; Le Gorrec, Madalen; Machillot, Paul; Neveu, Berangere; Thielens, Nicole M; Malissen, Bernard; Bonneville, Marc; Housset, Dominique.

In: Journal of Immunology, Vol. 183, No. 1, 2009, p. 430 - 437.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Structural bases for the affinity-driven selection of a public TCR against a dominant human cytomegalovirus epitope

AU - Gras, Stephanie

AU - Saulquin, Xavier

AU - Reiser, Jean-Baptiste

AU - Debeaupuis, Emilie

AU - Echasserieau, Klara

AU - Kissenpfennig, Adrien

AU - Legoux, Francois

AU - Chouquet, Anne

AU - Le Gorrec, Madalen

AU - Machillot, Paul

AU - Neveu, Berangere

AU - Thielens, Nicole M

AU - Malissen, Bernard

AU - Bonneville, Marc

AU - Housset, Dominique

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

UR - http://www.jimmunol.org/content/183/1/430.full.pdf+html

U2 - 10.4049/?jimmunol.0900556

DO - 10.4049/?jimmunol.0900556

M3 - Article

VL - 183

SP - 430

EP - 437

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 1

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