Loss of HTLV-1-specific CD8+ T-cell immunity in virus carriers predisposed to adult T-cell leukemia/lymphoma.

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 that elicit high frequencies of virus-specific CD8 + T cells in most virus carriers. Despite the virus being present in the tumor, HTLV-1-specific CD8 + cells are often undetectable in ATL. To characterize HTLV-1-specific CD8 + T cells during ATL development, we studied a subgroup 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 phenotype or absolute frequency of HTLV-1-specific CD8 + T cells. 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. In contrast, there was no difference in the frequency of CD8 + T cells specific for other viruses (cytomegalovirus, Epstein-Barr virus, influenza virus) 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.