Germinal center cytokine driven epigenetic control of Epstein-Barr virus latency gene expression

Liao, Yifei; Yan, Jinjie; Beri, Nina R.; Giulino-Roth, Lisa; Cesarman, Ethel; Gewurz, Benjamin E.

doi:10.1371/journal.ppat.1011939

Cited by 7 publications

(1 citation statement)

References 114 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One possibility explaining this novel result is that a subset of the most dividing CD8+ T cells is more susceptible to the epigenetic modifications induced by IL-15 signaling and result in the silencing the gene(s) coding for the CD8β chain(s). This view is not unlikely since a recent study has shown that IL- 15, via STAT3 and STAT5 signaling, mediated silencing of Epstein-Barr Nuclear Antigens (EBNA) via epigenetic effects ( 38 ).…”

Section: Discussionmentioning

confidence: 99%

In vitro IL-15-activated human naïve CD8+ T cells down-modulate the CD8β chain and become CD8αα T cells

Esgalhado,

Reste-Ferreira,

Weinhold

et al. 2024

Front. Immunol.

View full text Add to dashboard Cite

Antigen-driven human effector-memory CD8+ T cells expressing low levels of the CD8β chain have been previously described. However, little is known on a possible antigen-independent trigger. We have examined the impact that IL-15 has on the expression of CD8β on purified human naïve CD8+ T cells after CFSE labeling and culture with IL-15. As expected, IL-15 induced naïve CD8+ T cells to proliferate and differentiate. Remarkably, the process was associated with a cell-cycle dependent down-modulation of CD8β from the cell surface, leading to the generation of CD8αβlow and CD8αβ− (i.e., CD8αα) T cells. In contrast, expression of the CD8α chain remained steady or even increased. Neither IL-2 nor IL-7 reproduced the effect of IL-15. Determination of mRNA levels for CD8α and CD8β isoforms by qPCR revealed that IL-15 promoted a significant decrease in mRNA levels of the CD8β M-4 isoform, while levels of the M-1/M-2 isoforms and of CD8α increased. Noteworthy, CD8+ T cell blasts obtained after culture of CD8+ T cells with IL-15 showed a cell-cycle dependent increase in the level of the tyrosine kinase Lck, when compared to CD8+ T cells at day 0. This study has shown for the first time that IL-15 generates CD8αα+αβlow and CD8αα+αβ− T cells containing high levels of Lck, suggesting that they may be endowed with unique functional features.

show abstract

Section: Discussionmentioning

confidence: 99%

In vitro IL-15-activated human naïve CD8+ T cells down-modulate the CD8β chain and become CD8αα T cells

Esgalhado,

Reste-Ferreira,

Weinhold

et al. 2024

Front. Immunol.

View full text Add to dashboard Cite

show abstract

The DNA loop release factor WAPL suppresses Epstein-Barr virus latent membrane protein expression to maintain the highly restricted latency I program

Murray-Nerger,

Maestri,

Liu

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

Epstein-Barr virus (EBV) uses latency programs to colonize the memory B-cell reservoir, and each program is associated with human malignancies. However, knowledge remains incomplete of epigenetic mechanisms that maintain the highly restricted latency I program, present in memory and Burkitt lymphoma cells, in which EBNA1 is the only EBV-encoded protein expressed. Given increasing appreciation that higher order chromatin architecture is an important determinant of viral and host gene expression, we investigated roles of Wings Apart-Like Protein Homolog (WAPL), a host factor that unloads cohesins to control DNA loop size and that was discovered as an EBNA2-associated protein. WAPL knockout (KO) in Burkitt cells de-repressed LMP1 and LMP2A expression but not other EBV oncogenes to yield a viral program reminiscent of EBV latency II, which is rarely observed in B-cells. WAPL KO also increased LMP1/2A levels in latency III lymphoblastoid cells. WAPL KO altered EBV genome architecture, triggering formation of DNA loops between the LMP promoter region and the EBV origins of lytic replication (oriLyt). Hi-C analysis further demonstrated that WAPL KO reprograms EBV genomic DNA looping. LMP1 and LMP2A de-repression correlated with decreased histone repressive marks at their promoters. We propose that EBV coopts WAPL to negatively regulate latent membrane protein expression to maintain Burkitt latency I.

show abstract

Epstein-Barr Virus Latent Membrane Protein 1 Subverts IMPDH pathways to drive B-cell oncometabolism

Burton,

Liang,

Mitra

et al. 2024

Preprint

View full text Add to dashboard Cite

Epstein-Barr virus (EBV) is associated with multiple types of cancers, many of which express the key viral oncoprotein Latent Membrane Protein 1 (LMP1). LMP1 is the only EBV-encoded protein whose expression is sufficient to transform both epithelial and B-cells. Although metabolism reprogramming is a cancer hallmark, much remains to be learned about how LMP1 alters lymphocyte oncometabolism. To gain insights into key B-cell metabolic pathways subverted by LMP1, we performed systematic metabolomic analyses on B cells with conditional LMP1 expression. This approach highlighted that LMP highly induces de novo purine biosynthesis, with xanthosine-5-P (XMP) as one of the most highly LMP1-upregulated metabolites. Consequently, IMPDH inhibition by mycophenolic acid (MPA) triggered apoptosis of LMP1-expressing EBV-transformed lymphoblastoid cell lines (LCL), a key model for EBV-driven immunoblastic lymphomas. Whereas MPA instead caused growth arrest of Burkitt lymphoma cells with the EBV latency I program, conditional LMP1 expression triggered their apoptosis. Although both IMPDH isozymes are expressed in LCLs, only IMPDH2 was critical for LCL survival, whereas both contributed to proliferation of Burkitt cells with the EBV latency I program. Both LMP1 C-terminal cytoplasmic tail domains critical for primary human B-cell transformation were important for XMP production, and each contributed to LMP1-driven Burkitt cell sensitivity to MPA. MPA also de-repressed EBV lytic antigens including LMP1 in latency I Burkitt cells, highlighting crosstalk between the purine biosynthesis pathway and the EBV epigenome. These results suggest novel oncometabolism-based therapeutic approaches to LMP1-driven lymphomas.

show abstract

Germinal center cytokine driven epigenetic control of Epstein-Barr virus latency gene expression

Cited by 7 publications

References 114 publications

In vitro IL-15-activated human naïve CD8+ T cells down-modulate the CD8β chain and become CD8αα T cells

In vitro IL-15-activated human naïve CD8+ T cells down-modulate the CD8β chain and become CD8αα T cells

The DNA loop release factor WAPL suppresses Epstein-Barr virus latent membrane protein expression to maintain the highly restricted latency I program

Epstein-Barr Virus Latent Membrane Protein 1 Subverts IMPDH pathways to drive B-cell oncometabolism

Contact Info

Product

Resources

About