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

摘要

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.