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A Unique T-Cell Receptor Amino Acid Sequence Selected by Human T-Cell Lymphotropic Virus Type 1 Tax301-309-Specific Cytotoxic T Cells in HLA-A24:02-Positive Asymptomatic Carriers and Adult T-Cell Leukemia/Lymphoma Patients.

A Unique T-Cell Receptor Amino Acid Sequence Selected by Human T-Cell Lymphotropic Virus Type 1 Tax301-309-Specific Cytotoxic T Cells in HLA-A24:02-Positive Asymptomatic Carriers and Adult T-Cell Leukemia/Lymphoma Patients.
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Ishihara Y, Tanaka Y, Kobayashi S, Kawamura K, Nakasone H, Gomyo A, Hayakawa J, Tamaki M, Akahoshi Y, Harada N, Kusuda M, Kameda K, Ugai T, Wada H, Sakamoto K, Sato M, Terasako-Saito K, Kikuchi M, Kimura SI, Tanihara A, Kako S, Uchimaru K, Kanda Y,


Ishihara Y, Tanaka Y, Kobayashi S, Kawamura K, Nakasone H, Gomyo A, Hayakawa J, Tamaki M, Akahoshi Y, Harada N, Kusuda M, Kameda K, Ugai T, Wada H, Sakamoto K, Sato M, Terasako-Saito K, Kikuchi M, Kimura SI, Tanihara A, Kako S, Uchimaru K, Kanda Y, (click to view)

Ishihara Y, Tanaka Y, Kobayashi S, Kawamura K, Nakasone H, Gomyo A, Hayakawa J, Tamaki M, Akahoshi Y, Harada N, Kusuda M, Kameda K, Ugai T, Wada H, Sakamoto K, Sato M, Terasako-Saito K, Kikuchi M, Kimura SI, Tanihara A, Kako S, Uchimaru K, Kanda Y,

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Journal of virology 2017 09 1291(19) pii 10.1128/JVI.00974-17

Abstract

We previously reported that the T-cell receptor (TCR) repertoire of human T-cell lymphotropic virus type 1 (HTLV-1) Tax301-309-specific CD8(+) cytotoxic T cells (Tax301-309-CTLs) was highly restricted and a particular amino acid sequence motif, the PDR motif, was conserved among HLA-A*24:02-positive (HLA-A*24:02(+)) adult T-cell leukemia/lymphoma (ATL) patients who had undergone allogeneic hematopoietic cell transplantation (allo-HSCT). Furthermore, we found that donor-derived PDR(+) CTLs selectively expanded in ATL long-term HSCT survivors with strong CTL activity against HTLV-1. On the other hand, the TCR repertoires in Tax301-309-CTLs of asymptomatic HTLV-1 carriers (ACs) remain unclear. In this study, we directly identified the DNA sequence of complementarity-determining region 3 (CDR3) of the TCR-β chain of Tax301-309-CTLs at the single-cell level and compared not only the TCR repertoires but also the frequencies and phenotypes of Tax301-309-CTLs between ACs and ATL patients. We did not observe any essential difference in the frequencies of Tax301-309-CTLs between ACs and ATL patients. In the single-cell TCR repertoire analysis of Tax301-309-CTLs, 1,458 Tax301-309-CTLs and 140 clones were identified in this cohort. Tax301-309-CTLs showed highly restricted TCR repertoires with a strongly biased usage of BV7, and PDR, the unique motif in TCR-β CDR3, was exclusively observed in all ACs and ATL patients. However, there was no correlation between PDR(+) CTL frequencies and HTLV-1 proviral load (PVL). In conclusion, we have identified, for the first time, a unique amino acid sequence, PDR, as a public TCR-CDR3 motif against Tax in HLA-A*24:02(+) HTLV-1-infected individuals. Further investigations are warranted to elucidate the role of the PDR(+) CTL response in the progression from carrier state to ATL.IMPORTANCE ATL is an aggressive T-cell malignancy caused by HTLV-1 infection. The HTLV-1 regulatory protein Tax aggressively promotes the proliferation of HTLV-1-infected lymphocytes and is also a major target antigen for CD8(+) CTLs. In our previous evaluation of Tax301-309-CTLs, we found that a unique amino acid sequence motif, PDR, in CDR3 of the TCR-β chain of Tax301-309-CTLs was conserved among ATL patients after allo-HSCT. Furthermore, the PDR(+) Tax301-309-CTL clones selectively expanded and showed strong cytotoxic activities against HTLV-1. On the other hand, it remains unclear how Tax301-309-CTL repertoire exists in ACs. In this study, we comprehensively compared Tax-specific TCR repertoires at the single-cell level between ACs and ATL patients. Tax301-309-CTLs showed highly restricted TCR repertoires with a strongly biased usage of BV7, and PDR, the unique motif in TCR-β CDR3, was conserved in all ACs and ATL patients, regardless of clinical subtype in HTLV-1 infection.

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