In vitro infection of CD4+ T lymphocytes with HTLV-I generates immortalized cell lines coexpressing lymphoid and myeloid cell markers

Tricarico, Maria; Macchi, Beatrice; D’Atri, Stefania; Morrone, Stefania; Bonmassar, Enzo; Mp, Fuggetta; Graziani, Grazia

doi:10.1038/sj.leu.2401296

Cited by 8 publications

(7 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, similar results were obtained by coculturing JETWT35 cells with MT-2 cells ( Fig. 4C), which is another donor cell line widely used for HTLV-1 infection (38)(39)(40)(41)(42)(43). Interestingly, this inhibition of HTLV-1 transmission by PPS became inefficient when PPS was added to the coculture 12 h later ( Fig.…”

supporting

confidence: 79%

“…To this end, we used human umbilical vascular endothelial cells (HUVEC) because they are primary cells that resemble BBB cells and can be infected by HTLV-1 (44,45). We used lethally irradiated MT-2 cells as the donor cells to infect HUVEC, which is a widely used method of HTLV-1 infection (38)(39)(40)(41)(42). We first confirmed that there were no viable MT-2 cells 3 days after lethal irradiation by a trypan blue exclusion assay (data not shown).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Pentosan Polysulfate Demonstrates Anti-human T-Cell Leukemia Virus Type 1 ActivitiesIn VitroandIn Vivo

Yasunaga

Ohshima

et al. 2019

J Virol

View full text Add to dashboard Cite

Human T-cell leukemia virus type 1 (HTLV-1) infection causes T-cell leukemia and inflammatory diseases, most notably including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The underlying mechanism for the pathogenesis of HAM/TSP remains unclear. According to a recent clinical trial, a humanized antibody that targets CCR4 ϩ cells ameliorates inflammation by reducing the number of infected cells in the central nervous system; this result suggests that the transmigration of HTLV-1-infected cells plays a crucial role in HAM/TSP. Partly due to the blood-brain barrier, current treatments for HAM/TSP are mostly palliative. Pentosan polysulfate (PPS), a semisynthetic glycosaminoglycan, has recently been used to treat HAM/TSP and was found to alleviate the symptoms. In this study, we investigated the effect of PPS on HTLV-1-infected cells and provide evidence for its efficacy in HAM/TSP. PPS was cytotoxic to certain HTLV-1-infected cells and significantly suppressed HTLV-1 virion production. PPS also efficiently inhibited HTLV-1 cell-cell transmission in T cells. In addition, PPS blocked HTLV-1 infection of primary endothelial cells (human umbilical vascular endothelial cells) and suppressed the subsequent induction of proinflammatory cytokine expression. Furthermore, PPS was found to inhibit the adhesion and transmigration of HTLV-1-infected cells. We also confirmed the anti-HTLV-1 effect of PPS in vivo using two mouse models. PPS blocked HTLV-1 infection in a mouse model with peripheral blood mononuclear cell (PBMC)-humanized NOD-scid IL2Rgamma null (huPBMC NSG) mice. PPS was also found to suppress the development of dermatitis and lung damage in HTLV-1 bZIP factor (HBZ)-transgenic (HBZ-Tg) mice, an HTLV-1 transgenic mouse model in which the mice develop systemic inflammation. IMPORTANCE HTLV-1 is the first human retrovirus to have been identified and is endemic in certain areas worldwide. HTLV-1 infection leads to the development of an inflammatory disease called HAM/TSP, a myelopathy characterized by slowly progressive spastic paraparesis. There have been no effective therapeutics available for HAM/TSP, but recently, a semisynthetic glycosaminoglycan, named pentosan polysulfate (PPS), has been found to alleviate the symptoms of HAM/TSP. Here we conducted a comprehensive study on the effect of PPS both in vitro and in vivo. PPS demonstrated anti-HTLV-1 potential in infected cell lines, as shown by its suppressive effects on HTLV-1 replication and transmission and on the transmigration of infected T cells. Moreover, results obtained from two HTLV-1 mouse models demonstrate that PPS inhibits HTLV-1 infection and inflammation development in vivo. Our work offers insights into the treatment of HAM/TSP by PPS and also suggests its possible use for treating other HTLV-1-induced inflammatory diseases.

show abstract

supporting

confidence: 79%

mentioning

confidence: 99%

Pentosan Polysulfate Demonstrates Anti-human T-Cell Leukemia Virus Type 1 ActivitiesIn VitroandIn Vivo

Yasunaga

Ohshima

et al. 2019

J Virol

View full text Add to dashboard Cite

show abstract

“…Overexpression of cell adhesion molecules and chemokine receptors appear to facilitate organ infiltration of ATL cells. [42][43][44][55][56][57] One intriguing aspect of these findings was the expression of genes that were not normally expressed in T cells, 58,59 which was subsequently confirmed by expression array studies. The lineage-independent ectopic expression of many genes characterized ATL cells and strongly suggested abnormalities in epigenetic regulation that determined tissue-specific gene expression.…”

Section: 40mentioning

confidence: 99%

Adult T-cell leukemia: molecular basis for clonal expansion and transformation of HTLV-1–infected T cells

Watanabe

2017

Blood

142

117

View full text Add to dashboard Cite

Adult T-cell leukemia (ATL) is an aggressive T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1) that develops through a multistep carcinogenesis process involving 5 or more genetic events. We provide a comprehensive overview of recently uncovered information on the molecular basis of leukemogenesis in ATL. Broadly, the landscape of genetic abnormalities in ATL that include alterations highly enriched in genes for T-cell receptor–NF-κB signaling such as PLCG1, PRKCB, and CARD11 and gain-of function mutations in CCR4 and CCR7. Conversely, the epigenetic landscape of ATL can be summarized as polycomb repressive complex 2 hyperactivation with genome-wide H3K27 me3 accumulation as the basis of the unique transcriptome of ATL cells. Expression of H3K27 methyltransferase enhancer of zeste 2 was shown to be induced by HTLV-1 Tax and NF-κB. Furthermore, provirus integration site analysis with high-throughput sequencing enabled the analysis of clonal composition and cell number of each clone in vivo, whereas multicolor flow cytometric analysis with CD7 and cell adhesion molecule 1 enabled the identification of HTLV-1–infected CD4+ T cells in vivo. Sorted immortalized but untransformed cells displayed epigenetic changes closely overlapping those observed in terminally transformed ATL cells, suggesting that epigenetic abnormalities are likely earlier events in leukemogenesis. These new findings broaden the scope of conceptualization of the molecular mechanisms of leukemogenesis, dissecting them into immortalization and clonal progression. These recent findings also open a new direction of drug development for ATL prevention and treatment because epigenetic marks can be reprogrammed. Mechanisms underlying initial immortalization and progressive accumulation of these abnormalities remain to be elucidated.

show abstract

“…Thus, a low CD33 surface expression was found by flow cytometry on the earliest precursors of fetal thymocytes and a small subset of the postnatal CD34 ϩ human thymocytes [16]. Some CD33-expressing T lymphocytes were also detected by flow cytometry, such as CD4 ϩ T lymphocytes immortalized by human T cell leukemia virus-I infection [17], some human T cell clones (TCC) stimulated with anti-CD3 mAb plus interleukin (IL)-2 [18], or some polyclonal T cells stimulated with anti-CD3 mAb plus different cytokines [19]. With the same approach, a subset of CD33 ϩ natural killer (NK) cells could be found in the human umbilical cord [20], on some B cell precursors [21], and a subset of CD19 ϩ CD33 ϩ B cells in patients with Behcet's disease and sepsis [22].…”

Section: Introductionmentioning

confidence: 99%

A study of CD33 (SIGLEC-3) antigen expression and function on activated human T and NK cells: two isoforms of CD33 are generated by alternative splicing

Hernández‐Caselles

Martínez‐Esparza

Pérez-Oliva

et al. 2006

Journal of Leukocyte Biology

117

View full text Add to dashboard Cite

The expression of CD33, a restricted leukocyte antigen considered specific for myeloid lineage, has been studied extensively on lymphoid cells. We demonstrated that wide subsets of mitogen- or alloantigen-activated human T and natural killer (NK) cells express CD33 at protein and nucleic acid levels. CD33+ and CD33- T and NK cell populations showed identical surface expression of activation markers such as CD25, CD28, CD38, CD45RO, or CD95. Myeloid and lymphoid CD33 cDNA were identical. However, lymphoid CD33 protein had lower molecular weight, suggesting cell type-specific, post-translational modifications. Additionally, reverse transcriptase-polymerase chain reaction and Northern blot analysis showed an unknown CD33 isoform (CD33m) expressed on all CD33+ cell lines or T cell clones tested. CD33m was identical to CD33 (CD33M) in the signal peptide, the immunoglobulin (Ig) domain C2, the transmembrane, and the cytoplasmic regions but lacked the extracellular ligand-binding variable Ig-like domain encoded by the second exon. CD33m mRNA was mostly detected on NKL and myeloid cell lines but poorly expressed on B cell lines and T lymphocytes. The CD33m extracellular portion was successfully expressed as a soluble fusion protein on transfected human cells, suggesting a functional role on cell membranes. Cross-linking of CD33 diminished the cytotoxic activity of NKL cells against K562 and P815 target cells, working as an inhibitory receptor on NK cells. These data demonstrate that CD33 expression is not restricted to the myeloid lineage and could exist as two different splicing variants, which could play an important role in the regulation of human lymphoid and myeloid cells.

show abstract

In vitro infection of CD4+ T lymphocytes with HTLV-I generates immortalized cell lines coexpressing lymphoid and myeloid cell markers

Cited by 8 publications

References 31 publications

Pentosan Polysulfate Demonstrates Anti-human T-Cell Leukemia Virus Type 1 ActivitiesIn VitroandIn Vivo

Pentosan Polysulfate Demonstrates Anti-human T-Cell Leukemia Virus Type 1 ActivitiesIn VitroandIn Vivo

Adult T-cell leukemia: molecular basis for clonal expansion and transformation of HTLV-1–infected T cells

A study of CD33 (SIGLEC-3) antigen expression and function on activated human T and NK cells: two isoforms of CD33 are generated by alternative splicing

Contact Info

Product

Resources

About