Structural bases for the affinity-driven selection of a public TCR against a dominant human cytomegalovirus epitope.
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.
Gras
Stéphanie
S
Institut de Biologie Structurale Jean-Pierre Ebel, CEA, CNRS, UJF, PSB, Grenoble, France.
Saulquin
Xavier
X
Reiser
Jean-Baptiste
JB
Debeaupuis
Emilie
E
Echasserieau
Klara
K
Kissenpfennig
Adrien
A
Legoux
François
F
Chouquet
Anne
A
Le Gorrec
Madalen
M
Machillot
Paul
P
Neveu
Bérangère
B
Thielens
Nicole
N
Malissen
Bernard
B
Bonneville
Marc
M
Housset
Dominique
D
D020816:Amino Acid Motifs; D002999:Clone Cells; D018360:Crystallography, X-Ray; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000276:immunology / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015234:HLA-A Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015789:HLA-A2 Antigen; D006801:Humans; D016056:Immunodominant Epitopes / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D014775:Virus Activation / Q000276:immunology
D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D016056:Immunodominant Epitopes; D010455:Peptides; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; D014763:Viral Matrix Proteins; C065418:cytomegalovirus matrix protein 65kDa