Prevalent role of TCR α-chain in the selection of the preimmune repertoire specific for a human tumor-associated self-antigen

被引:65
作者
Dietrich, PY
Le Gal, FA
Dutoit, V
Pittet, MJ
Trautman, L
Zippelius, A
Cognet, I
Widmer, V
Walker, PR
Michielin, O
Guillaume, P
Connerotte, T
Jotereau, F
Coulie, PG
Romero, P
Cerottini, JC
Bonneville, M
Valmori, D
机构
[1] Hop Orthoped, Ludwig Inst Canc Res, Div Clin Oncoimmunol, CH-1011 Lausanne, Switzerland
[2] Univ Hosp Geneva, Div Oncol, Lab Tumor Immunol, Geneva, Switzerland
[3] INSERM, U463, Inst Biol, Nantes, France
[4] Univ Lausanne, Ludwig Inst Canc Res, CH-1066 Epalinges, Switzerland
[5] Catholic Univ Louvain, Cellular Genet Unit, Brussels, Belgium
关键词
D O I
10.4049/jimmunol.170.10.5103
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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 Valpha- than Vbeta-restricted usage. Whether Valpha usage is narrowed during immune responses to Ag or if, on the contrary, restricted Valpha 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 Vbeta usage, but a preferential Valpha 2.1 usage. Restricted Valpha 2.1 usage was also found among single CD8(+) A2/melan-A multimer(+) thymocytes, indicating that Valpha-restricted selection takes place in the thymus. Valpha 2.1 usage, however, was independent from functional avidity of Ag recognition. Thus, interaction of the pMHC complex with selected Valpha-chains contributes to set the broad Ag specificity, as underlined by preferential binding of A2/melan-A multimers to Valpha 2.1-bearing TCRs, whereas functional outcomes result from the sum of these with other interactions between pMHC complex and TCR.
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页码:5103 / 5109
页数:7
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