Retrovirus-induced leukemia – hijack of T-cell activation mechanisms revealed by single-cell analysis

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 progressing to develop adult T-cell leukemia/lymphoma (ATL). Whilst HTLV-1 alters cellular differentiation, activation and survival, it is unknown whether and how these changes contribute to malignant transformation of infected T-cells. In this study, we used single-cell RNA-Seq and TCR-Seq to investigate T-cell differentiation and HTLV-1-mediated transformation processes. We analyzed 87,742 single cells from peripheral blood of 12 infected and 3 uninfected individuals. Using multiple independent bioinformatic methods, we demonstrated that naive T-cells dynamically change into activated T-cells including infected cells, which seamlessly transitioned into ATL cells characterized by clonally expanded, highly-activated T-cells. Notably, the more activated ATL cells are, the more they acquire Treg signatures. Intriguingly, HLA class II genes were uniquely induced in infected cells, further upregulated in ATL cells and was induced by viral protein Tax. Functional assays revealed that by upregulating HLA class II, HTLV-1-infected cells can act as tolerogenic antigen presenting cells (APCs) 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 single-cell level.

TRAF3IP3 promotes glioma progression through the ERK signaling pathway

“…Previous studies have shown that TRAF3IP3 plays a vital role in IFN-mediated antiviral innate immunity and participates in RIG-I-MAVS-mediated antiviral signaling (22). However, it is unclear which signaling pathway is activated by TRAF3IP3 in glioma and whether other crosstalk pathways are involved.…”

“…Ubiquitin-mediated proteolysis is reportedly associated with pancreatic cancer metastasis (21). 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) (22). Glioblastoma is one of the most aggressive and frequent primary brain tumors.…”

T cell receptor repertoire analysis in HTLV-1-associated diseases

“…As both TCR-a and TCR-b sequences are typically expressed in conjunction and necessarily must interact with CD3 for the differentiation and survival of T cells, these skewed TCR clones may coincide with previous findings of reduced CD3 protein expression in ATL (81). A recent advance of TCR repertoire analysis with multiple bioinformatics analysis at single cell level also demonstrated that HTLV-1-infected cells in an activated state further transformed into ATL cells, which are characterized as clonally expanded, highly activated T cells (78). In addition, while healthy individuals harbored T cells with an activated phenotype, in ATL, infected T cells and ATL cells became spontaneously activated, acquired a regulatory T cell phenotype, and subsequently progressed to a state of extreme activation, which was maintained throughout the ATL phase (78).…”

“…A recent advance of TCR repertoire analysis with multiple bioinformatics analysis at single cell level also demonstrated that HTLV-1-infected cells in an activated state further transformed into ATL cells, which are characterized as clonally expanded, highly activated T cells (78). In addition, while healthy individuals harbored T cells with an activated phenotype, in ATL, infected T cells and ATL cells became spontaneously activated, acquired a regulatory T cell phenotype, and subsequently progressed to a state of extreme activation, which was maintained throughout the ATL phase (78). Thus, new technologies and bioinformatics tools at single cell level will further improve our ability to identify mechanistic pathways responsible for the in vivo transformation of HTLV-1infected T cells into leukemic cells.…”