T Cell Receptor Vβ Staining Identifies the Malignant Clone in Adult T cell Leukemia and Reveals Killing of Leukemia Cells by Autologous CD8+ T cells

Abstract

There is growing evidence that CD8+ cytotoxic T lymphocyte (CTL) responses can contribute to long-term remission of many malignancies. The etiological agent of adult T-cell leukemia/lymphoma (ATL), human T lymphotropic virus type-1 (HTLV-1), contains highly immunogenic CTL epitopes, but ATL patients typically have low frequencies of cytokine-producing HTLV-1-specific CD8+ cells in the circulation. It remains unclear whether patients with ATL possess CTLs that can kill the malignant HTLV-1 infected clone. Here we used flow cytometric staining of TCRVβ and cell adhesion molecule-1 (CADM1) to identify monoclonal populations of HTLV-1-infected T cells in the peripheral blood of patients with ATL. Thus, we quantified the rate of CD8+-mediated killing of the putative malignant clone in ex vivo blood samples. We observed that CD8+ cells from ATL patients were unable to lyse autologous ATL clones when tested directly ex vivo. However, short in vitro culture restored the ability of CD8+ cells to kill ex vivo ATL clones in some donors. The capacity of CD8+ cells to lyse HTLV-1 infected cells which expressed the viral sense strand gene products was significantly enhanced after in vitro culture, and donors with an ATL clone that expressed the HTLV-1 Tax gene were most likely to make a detectable lytic CD8+ response to the ATL cells. We conclude that some patients with ATL possess functional tumour-specific CTLs which could be exploited to contribute to control of the disease.

Human T-lymphotropic virus type 1 (HTLV-1) and cellular immune response in HTLV-1-associated myelopathy/tropical spastic paraparesis

“…In addition, longitudinal analysis of TCR repertoires demonstrated a correlation of the TCR clonal expansion with HTLV-1 proviral load. ATLL patients also showed monoclonal TCRs compared with ACs, and clonality data observed based on TCR repertoires were completely consistent with clonality analysis based on provirus integration sites (Rowan et al 2016;Farmanbar et al 2019). Recently, Tax 301-309 -specific CTL in HLA-A*2402 ATLL patients and ACs shared highly restricted TCR repertoires by the single-cell analysis (Ishikawa et al 2017).…”

Switching and loss of cellular cytokine producing capacity characterize in vivo viral infection and malignant transformation in human T- lymphotropic virus type 1 infection

“…In ATL the majority of infected cells are derived from a single dominant leukemic clone amongst thousands of non-dominant clones whilst thousands of non-dominant clones of varying size contribute to the total infection burden in non-ATL HTLV-1 infection [ 29 , 36 , 37 , 46 ]. CD4+CCR4+CD26-CD7- cells have been shown to harbour the dominant clone in ATL and these cells are also present in non-malignant HTLV-1 infection[ 23 , 27 , 47 , 48 ]. We have demonstrated that these cells are made up of hundreds of non-dominant clones (‘ATL-like’ cells) in patients with non-malignant HTLV-1 infection and a single dominant clone (putative ATL cells) amongst tens of smaller non-dominant clones (‘ATL-like’ cells) in patients with ATL.…”

Quantification of HTLV-1 reverse transcriptase activity in ATL patients treated with zidovudine and interferon-α

“…0.7 is characteristic of ATL. 22 The HTLV-1 proviral loads were as follows: ATL4 (pretherapy, 57.12%; posttherapy, 53.47%); ATL7 (pretherapy, 11.65%; posttherapy, 13.93%). OD-Bkg, optical density-background.…”