Viral antigen mismatch affects antiviral T-cell response and may impair immunotherapeutic efficacy against ATL

Human T-cell leukemia virus type 1 (HTLV-1) has the potential to transform primary CD4 + T cells in vitro within a short time; however, the majority of infected individuals maintain an asymptomatic and disease-free condition, suggesting the existence of an equilibrium between the proliferation of infected cells and host immunity. The decline in anti-viral immunity contributes to the transformation of the infected cells, leading to the development of adult T-cell leukemia/lymphoma (ATL). This study identified a variation in a major viral antigen, HTLV-1 Tax, in human leukocyte antigen-A24 (HLA-A24) positive individuals. Two variants of Tax 301-309 peptides, SFHNLHLLF (Tax 301-309 A) and SFHSLHLLF (Tax 301-309 B) were found to induce distinct T-cell immune responses in HLA-A24 positive individuals. There was a disparity between two Tax 301-309 peptides in the detection of anti-Tax 301-309 cytotoxic T-lymphocytes (CTLs) binding to A24/peptide multimers by flow cytometry analysis. More importantly, over half of the anti-Tax TCRs of anti-Tax CTLs from infected individuals did not recognize mismatched Tax 301-309 peptides by Enzyme-Linked Immunospot (ELISpot) assay using Jurkat T cells expressing the anti-Tax 301-309 specific TCR. These findings underscore the importance of matching the viral antigen epitope type in T-cell-based immunotherapy against ATL by using viral antigen Tax. Key points Epitope heterogeneity in the major viral antigen in HTLV-1 infection causes different T-cell responses in infected individuals. Recommended guideline; performing virus typing to obtain optimal efficacy in T-cell-mediated immunotherapy against the viral antigen Tax