HTLV-1 infection promotes excessive T cell activation and transformation into adult T cell leukemia/lymphoma
Benjy J.Y. Tan, … , Masahiro Ono, Yorifumi Satou
Benjy J.Y. Tan, … , Masahiro Ono, Yorifumi Satou
Published December 15, 2021
Citation Information: J Clin Invest. 2021;131(24):e150472. https://doi.org/10.1172/JCI150472.
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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 8

HTLV-1–infected cells can present antigen to responder CD4+ T cells and induce anergy-related genes.

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HTLV-1–infected cells can present antigen to responder CD4+ T cells and ...
(A) Bar graph shows the antigen-presenting capabilities of the different HTLV-1–infected T cell lines. Jurkat cells expressing the HLA-DP4–restricted TCR (clone 9) specific for cancer testis antigen WT1 were stimulated with peptide-pulsed cell lines. CLIP peptide was used as a negative control. (B) Experimental scheme to evaluate T cell status after antigen-specific stimulation by HTLV-1–infected CD4+ T cells. Similar results were obtained from at least 2 independent donor samples. (C) Bar graphs show the antigen-presenting capabilities of different APCs from an HLA-DP4– donor and HLA-DP4+ donor. Normal CD4+ T cells, infected CD4+ T cells, and non–T cells from ACs were prepared as CADM1–CD4+, CADM1+CD4+, and CD4/CD8-depleted PBMCs, respectively. Clone 9–transduced primary T cells were stimulated with APCs pulsed with peptides. Histograms show the expression of HLA class II in normal (CADM1–CD4+) and infected CD4+ T cells (CADM1+CD4+). SFU, spot-forming units. (D) Bar graphs show the expression of T cell anergy–related genes in responder T cells after stimulation with non–T cells (conventional APCs) or HTLV-1–infected CD4+ T cells expressing HLA class II molecules. Non–T cells and infected CD4+ T cells were prepared from HLA-DP4+ ACs as CD3-depleted and CADM1+CD4+ PBMCs, respectively. For each APC, the relative expression of each gene was calculated by normalization against the expression level of HPRT1 in the APCs stimulated with a negative control peptide (CLIP). n = 3 (A, C, and D). Data indicate the mean ± SD. *P < 0.05, **P < 0.01, and ***P < 0.001, by unpaired, 2-tailed Student’s t test.