title: Universal cytotoxic activity of a HTLV-1 Tax-specific T cell clone from an HLA-A*24:02⁺ patient with adult T-cell leukemia against a variety of HTLV-I-infected T-cells.
abstract: Adult T cell leukemia/lymphoma (ATL) is an aggressive mature T cell malignancy that is causally associated with human T cell lymphotropic virus type 1 (HTLV-1) infection. The HTLV-1 regulatory protein Tax aggressively accelerates the proliferation of host cells and is also an important target antigen for CD8(+) cytotoxic T cells (CTLs). We previously reported that several predominant HLA-A*24:02-restricted HTLV-1 Tax301-309-specific CTL clones commonly expressed a particular amino acid sequence motif (P-D-R) in complementarity-determining region 3 of T-cell receptor (TCR)-β chain among unrelated ATL patients who underwent allogeneic stem cell transplantation (allo-HSCT). Furthermore, a PDR-motif(+) CTL clone persistently existed in a long-term survivor as a central CTL clone with strong CTL activities after HSCT. Although a larger analysis of the relationship between PDR-motif(+) CTLs and the clinical course is required, the expression of PDR-motif(+) TCR on CD8(+) T cells may play a critical role in the management of anti-HTLV-1 activities for HLA-A24:02(+) ATL patients. Therefore, in this study, we prepared an HTLV-1 Tax301-309 peptide-specific CTL clone (HT-9) expressing PDR-motif(+) TCR isolated from a long-term survivor after HSCT, and evaluated its CTL activity against a variety of HTLV-1-infected T-cells from HLA-A*24:02(+) ATL patients. Before the assay of CTL function, we confirmed that HT-9 expressed less-differentiated effector-memory phenotypes (CD45RA(-)CCR7(-)CD27(+)CD28(+/-)CD57(+/-)) and T-cell exhaustion marker PD-1(+). In assays of CTL function, HT-9 recognized HTLV-1 Tax in an HLA-restricted fashion and demonstrated strong CTL activities against a variety of HTLV-1-infected T-cells from HLA-A*24:02(+) ATL patients regardless of whether the sources were autologous or allogeneic, but not normal cells. These data indicate that PDR-motif(+) TCR could be an important TCR candidate for TCR-gene immunotherapy for HLA-A24:02(+) ATL patients, provided that the CTL activities against HTLV-1 are reproduced in in vivo experiments using mouse models.
authors.affiliation: Division of Hematology, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
authors.forename: Yukie
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Division of Hematology, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Yamazaki
authors.affiliation: Division of Hematology, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
authors.forename: Kiriko
authors.initials: K
authors.lastname: Terasako-Saito
authors.affiliation: Division of Hematology, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Nakasone
authors.affiliation: Division of Hematology, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Akahoshi
authors.affiliation: Division of Hematology, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Nakano
authors.affiliation: Division of Hematology, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
authors.forename: Tomotaka
authors.initials: T
authors.lastname: Ugai
authors.affiliation: Division of Hematology, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Wada
authors.affiliation: Division of Hematology, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Yamasaki
authors.affiliation: Division of Hematology, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Ishihara
authors.affiliation: Division of Hematology, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Kawamura
authors.affiliation: Division of Hematology, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
authors.forename: Kana
authors.initials: K
authors.lastname: Sakamoto
authors.affiliation: Division of Hematology, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ashizawa
authors.affiliation: Division of Hematology, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Sato
authors.affiliation: Division of Hematology, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
authors.forename: Shun-ichi
authors.initials: S
authors.lastname: Kimura
authors.affiliation: Division of Hematology, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
authors.forename: Misato
authors.initials: M
authors.lastname: Kikuchi
authors.affiliation: Division of Hematology, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kako
authors.affiliation: Division of Hematology, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Kanda
authors.affiliation: Division of Hematology, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
authors.forename: Aki
authors.initials: A
authors.lastname: Tanihara
authors.affiliation: Division of Hematology, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Nishida
authors.affiliation: Division of Hematology, Saitama Medical Center, Jichi Medical University, Saitama, Japan. Electronic address: ycanda-tky@umin.ac.jp.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Kanda
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics; D015703:Antigens, CD / Q000378:metabolism; D002999:Clone Cells; D003602:Cytotoxicity, Immunologic; D016356:Gene Products, tax / Q000276:immunology; D015316:Genetic Therapy; D059871:HLA-A24 Antigen / Q000276:immunology; D015490:HTLV-I Infections / Q000276:immunology* / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation; D015368:Human T-lymphotropic virus 1 / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D007167:Immunotherapy / Q000379:methods*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D011485:Protein Binding; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000378:metabolism; D037182:T-Cell Antigen Receptor Specificity; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D016356:Gene Products, tax; C438506:HLA-A*24:02 antigen; D059871:HLA-A24 Antigen; C105992:PDCD1 protein, human; D010446:Peptide Fragments; D061026:Programmed Cell Death 1 Receptor; D016693:Receptors, Antigen, T-Cell, alpha-beta; C514970:tax protein, Human T-lymphotrophic virus 1
keywords: Adult T cell leukemia/lymphoma; Human T cell lymphotropic virus type 1; Immunotherapy; T-cell receptor; Tax