Prevalent role of TCR alpha-chain in the selection of the preimmune repertoire specific for a human tumor-associated self-antigen.
The specificity of recognition of pMHC complexes by T lymphocytes is determined by the V regions of the TCR alpha- and beta-chains. Recent experimental evidence has suggested that Ag-specific TCR repertoires may exhibit a more V alpha- than V beta-restricted usage. Whether V alpha usage is narrowed during immune responses to Ag or if, on the contrary, restricted V alpha usage is already defined at the early stages of TCR repertoire selection, however, has remained unexplored. Here, we analyzed V and CDR3 TCR regions of single circulating naive T cells specifically detected ex vivo and isolated with HLA-A2/melan-A peptide multimers. Similarly to what was previously observed for melan-A-specific Ag-experienced T cells, we found a relatively wide V beta usage, but a preferential V alpha 2.1 usage. Restricted V alpha 2.1 usage was also found among single CD8(+) A2/melan-A multimer(+) thymocytes, indicating that V alpha-restricted selection takes place in the thymus. V alpha 2.1 usage, however, was independent from functional avidity of Ag recognition. Thus, interaction of the pMHC complex with selected V alpha-chains contributes to set the broad Ag specificity, as underlined by preferential binding of A2/melan-A multimers to V alpha 2.1-bearing TCRs, whereas functional outcomes result from the sum of these with other interactions between pMHC complex and TCR.
Division of Oncology, Laboratory of Tumor Immunology, University Hospital, Geneva, Switzerland. pierre-yves.dietrich@hcuge.ch
Pierre-Yves
PY
Dietrich
Frédérique-Anne
FA
Le Gal
Valérie
V
Dutoit
Mikäel J
MJ
Pittet
Lydie
L
Trautman
Alfred
A
Zippelius
Isabelle
I
Cognet
Valérie
V
Widmer
Paul R
PR
Walker
Olivier
O
Michielin
Philippe
P
Guillaume
Thierry
T
Connerotte
Francine
F
Jotereau
Pierre G
PG
Coulie
Pedro
P
Romero
Jean-Charles
JC
Cerottini
Marc
M
Bonneville
Danila
D
Valmori
D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm; D001324:Autoantigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002999:Clone Cells; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015332:Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor / Q000502:physiology*; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor / Q000502:physiology; D015789:HLA-A2 Antigen / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000378:metabolism; D006801:Humans; D058965:MART-1 Antigen; D008545:Melanoma / Q000235:genetics / Q000276:immunology*; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D058965:MART-1 Antigen; C548667:MLANA protein, human; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D016693:Receptors, Antigen, T-Cell, alpha-beta