HTLV-1 infection promotes excessive T cell activation and transformation into adult T cell leukemia/lymphoma
Benjy J.Y. Tan, Kenji Sugata, Omnia Reda, Misaki Matsuo, Kyosuke Uchiyama, Paola Miyazato, Vincent Hahaut, Makoto Yamagishi, Kaoru Uchimaru, Yutaka Suzuki, Takamasa Ueno, Hitoshi Suzushima, Hiroo Katsuya, Masahito Tokunaga, Yoshikazu Uchiyama, Hideaki Nakamura, Eisaburo Sueoka, Atae Utsunomiya, Masahiro Ono, Yorifumi Satou
Benjy J.Y. Tan, Kenji Sugata, Omnia Reda, Misaki Matsuo, Kyosuke Uchiyama, Paola Miyazato, Vincent Hahaut, Makoto Yamagishi, Kaoru Uchimaru, Yutaka Suzuki, Takamasa Ueno, Hitoshi Suzushima, Hiroo Katsuya, Masahito Tokunaga, Yoshikazu Uchiyama, Hideaki Nakamura, Eisaburo Sueoka, Atae Utsunomiya, Masahiro Ono, Yorifumi Satou
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Research Article Infectious disease Virology

HTLV-1 infection promotes excessive T cell activation and transformation into adult T cell leukemia/lymphoma

Abstract

Human T cell leukemia virus type 1 (HTLV-1) mainly infects CD4+ T cells and induces chronic, persistent infection in infected individuals, with some developing adult T cell leukemia/lymphoma (ATL). HTLV-1 alters cellular differentiation, activation, and survival; however, it is unknown whether and how these changes contribute to the malignant transformation of infected cells. In this study, we used single-cell RNA-sequencing and T cell receptor–sequencing to investigate the differentiation and HTLV-1–mediated transformation of T cells. We analyzed 87,742 PBMCs from 12 infected and 3 uninfected individuals. Using multiple independent bioinformatics methods, we demonstrated the seamless transition of naive T cells into activated T cells, whereby HTLV-1–infected cells in an activated state further transformed into ATL cells, which are characterized as clonally expanded, highly activated T cells. Notably, the greater the activation state of ATL cells, the more they acquire Treg signatures. Intriguingly, the expression of HLA class II genes in HTLV-1–infected cells was uniquely induced by the viral protein Tax and further upregulated in ATL cells. Functional assays revealed that HTLV-1–infected cells upregulated HLA class II molecules and acted as tolerogenic antigen-presenting cells to induce anergy of antigen-specific T cells. In conclusion, our study revealed the in vivo mechanisms of HTLV-1–mediated transformation and immune escape at the single-cell level.

Authors

Benjy J.Y. Tan, Kenji Sugata, Omnia Reda, Misaki Matsuo, Kyosuke Uchiyama, Paola Miyazato, Vincent Hahaut, Makoto Yamagishi, Kaoru Uchimaru, Yutaka Suzuki, Takamasa Ueno, Hitoshi Suzushima, Hiroo Katsuya, Masahito Tokunaga, Yoshikazu Uchiyama, Hideaki Nakamura, Eisaburo Sueoka, Atae Utsunomiya, Masahiro Ono, Yorifumi Satou

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Figure 6

Pseudotime analysis of a paired ATL sample.

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Pseudotime analysis of a paired ATL sample. (A) Schematic shows pseudoti...
(A) Schematic shows pseudotime analysis of the 3 HDs and the 1 paired ATL sample. (B) Plot showing the clusters and pseudotime trajectory; from left to right, clusters are colored by pseudotime, clinical condition, and most expanded clone for each ATL. (C) Plot shows the RNA velocity in Seurat-identified clusters. The inset box is colored by pseudotime as shown in B. (D) Expression dynamics of HLA class II and related genes along the pseudotime axis. The colors of the dots represent the cells’ position along the pseudotime axis as in B. (E) Split heatmap shows the expression profile of genes that vary as a function of pseudotime and are branch dependent. The pseudotime trajectory begins from the middle of the heatmap (gray boxes) and moves to the left for the top branch and to the right for the bottom branch. The start of the arrow indicates the bifurcation point in the trajectory in B. Hierarchical clustering grouped the genes into 5 clusters, which are indicated by outlined colored boxes on the right, along with their enriched pathways. (F) Volcano plot shows the DEGs between the top and bottom branches. The genes are colored according to the clusters shown in the split heatmap in E. (G) The dot and line graph shows the change in frequencies of variant alleles across 2 time points, as detected using targeted exome sequencing, for the CADM1+CD7–/+ cell population from the paired ATL case. Genes showing huge changes in frequency are labeled. The pie chart at the bottom shows the ATL cells’ clonality identified by the HTLV-1 integration site. (H) Bar graph shows the frequency of the CSNK1A1 variant by trajectory branch detected in the scRNA-Seq data.