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.
Dietrich
Pierre-Yves
PY
Division of Oncology, Laboratory of Tumor Immunology, University Hospital, Geneva, Switzerland. pierre-yves.dietrich@hcuge.ch
Le Gal
Frédérique-Anne
FA
Dutoit
Valérie
V
Pittet
Mikäel J
MJ
Trautman
Lydie
L
Zippelius
Alfred
A
Cognet
Isabelle
I
Widmer
Valérie
V
Walker
Paul R
PR
Michielin
Olivier
O
Guillaume
Philippe
P
Connerotte
Thierry
T
Jotereau
Francine
F
Coulie
Pierre G
PG
Romero
Pedro
P
Cerottini
Jean-Charles
JC
Bonneville
Marc
M
Valmori
Danila
D
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