Potential contribution of a novel tax epitope-specific CD4⁺ T cells to graft-versus-tax effect in adult T cell leukemia patients after allogeneic hematopoietic stem cell transplantation

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for adult T cell leukemia/lymphoma (ATL) caused by human T cell leukemia virus type1 (HTLV-1). We previously reported that Tax-specific CD8⁺ cytotoxic T lymphocyte (CTL) contributed to graft-versus-ATL effects in ATL patients after allo-HSCT. However, the role of HTLV-1-specific CD4⁺ T cells in the effects remains unclear. In this study, we showed that Tax-specific CD4⁺ as well as CD8⁺ T cell responses were induced in some ATL patients following allo-HSCT. To further analyze HTLV-1-specific CD4⁺ T cell responses, we identified a novel HLA-DRB1^*0101- restricted epitope, Tax155-167, recognized by HTLV-1-specific CD4⁺ Th1-like cells, a major population of HTLV-1-specific CD4⁺ T cell line, which was established from an ATL patient at 180 d after allo-HSCT from an unrelated seronegative donor by in vitro stimulation with HTLV-1-infected cells from the same patient. Costimulation of PBMCs with both the identified epitope (Tax155-167) and known CTL epitope peptides markedly enhanced the expansion of Tax-specific CD8 ⁺ T cells in PBMCs compared with stimulation with CTL epitope peptide alone in all three HLA-DRB1^*0101⁺ patients post-allo-HSCT tested. In addition, direct detection using newly generated HLA-DRB1^*0101/Tax155-167 tetramers revealed that Tax155-167-specific CD4⁺ T cells were present in all HTLV-1- infected individuals tested, regardless of HSCT. These results suggest that Tax155-167 may be the dominant epitope recognized by HTLV-1-specific CD4⁺ T cells in HLA-DRB1^*0101⁺-infected individuals and that Tax-specific CD4⁺ T cells may augment the graft-versus-Tax effects via efficient induction of Tax-specific CD8⁺ T cell responses.