HTLV-1 infection promotes excessive T cell activation and transformation into adult T cell leukemia/lymphoma
HTLV-1 infection promotes excessive T cell activation and transformation into adult T cell leukemia/lymphoma
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DOI：
10.1172/jci150472
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发表时间：
2021-12-15
影响因子：
15.9
通讯作者：
Satou, Yorifumi
中科院分区：
文献类型：
--
作者：
Tan, Benjy J. Y.;Sugata, Kenji;Satou, Yorifumi
人类T细胞白血病病毒1型（HTLV-1）主要感染CD 4（+）T细胞，并在感染个体中诱导慢性持续感染，其中一些发展为成人T细胞白血病/淋巴瘤（ATL）。HTLV-1改变细胞分化、活化和存活;然而，尚不清楚这些变化是否以及如何导致受感染细胞的恶性转化。在本研究中，我们使用单细胞RNA测序和T细胞受体测序来研究T细胞的分化和HTLV-1介导的转化。我们分析了来自12名感染者和3名未感染者的87，742个PBMC。使用多种独立的生物信息学方法，我们证明了初始T细胞向活化T细胞的无缝转变，由此处于活化状态的HTLV-1感染的细胞进一步转化为ATL细胞，其特征在于克隆扩增的高度活化的T细胞。值得注意的是，ATL细胞的激活状态越强，它们获得的Treg特征就越多。有趣的是，在HTLV-1感染的细胞中HLA II类基因的表达是由病毒蛋白Tax独特诱导的，并在ATL细胞中进一步上调。功能分析显示，HTLV-1感染的细胞上调HLA II类分子，并作为致耐受性抗原呈递细胞诱导抗原特异性T细胞的无能。总之，我们的研究揭示了HTLV-1介导的转化和免疫逃逸在单细胞水平上的体内机制。
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.