Loss of HTLV-1–specific CD8⁺ T-cell immunity in virus-carriers predisposed to adult T-cell leukemia/lymphoma
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Adult T-cell Leukemia/Lymphoma (ATL) is caused by chronic infection with Human T-lymphotropic virus type-1 (HTLV-1). HTLV-1 contains highly immunogenic CD8+ T-cell epitopes which elicit high frequencies of virus-specific CD8+ T-cells in most virus-carriers. Despite the virus being present in the tumour, HTLV-1-specific CD8+ cells are often undetectable in ATL. To characterise HTLV-1-specific CD8+ T-cells during ATL development, we studied a sub-group of people living with asymptomatic HTLV-1 infection at very high risk of developing ATL. These so- called ‘high-risk’ carriers have suspected premalignant lesions: expanded, HTLV-1-infected ‘ATL-like’ clones circulating in their peripheral blood. Compared to viral antigen-burden matched controls, high-risk carriers had significantly fewer Tax-specific IFN-γ+CD8+ cells in peripheral blood. Furthermore, ex vivo CD8+ T-cells from high-risk carriers did not efficiently kill autologous HTLV-1-infected T-cells, including premalignant ATL-like clones. We stained Tax11–19/HLA-A*0201 pentamer+CD8+ T-cells to test whether the low frequencies of functional CD8+ T-cells resulted from the phenotype or absolute frequency of HTLV-1-specific CD8+ T-cells. Again, high-risk carriers had significantly lower frequencies of Tax11–19/HLA-A*0201 pentamer+CD8+ T-cells than controls, but we observed no difference in effector function, memory phenotype or expression of checkpoint control molecules (PD-1, TIGIT, TIM-3, LAG-3, CTLA-4). In contrast, there was no difference in the frequency of CD8+ T-cells specific for other viruses (CMV, EBV, Flu) between high-risk carriers and controls. This is the first report of HTLV-1-specific immune dysregulation in the premalignant stage of ATL. Low frequencies of HTLV-1-specific CD8+ T-cells may contribute to ATL development, and may be a novel therapeutic target for ATL prevention.
Date Issued
2026-08-01
Date Acceptance
2026-03-29
Citation
Blood Neoplasia, 2026, 3 (3)
ISSN
2950-3280
Publisher
Elsevier BV
Journal / Book Title
Blood Neoplasia
Volume
3
Issue
3
Copyright Statement
© 2026 American Society of Hematology. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
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Publication Status
Published
Article Number
100235
Date Publish Online
2026-04-27