Human memory CD8 T cell effector potential is epigenetically preserved during in vivo homeostasis

Abdelsamed, Hossam; Moustaki, Ardiana; Fan, Yiping; Dogra, Pranay; Ghoneim, Hazem E.; Zebley, Caitlin C.; Triplett, Brandon M.; Sékaly, Rafick‐Pierre; Youngblood, Benjamin A.

doi:10.1084/jem.20161760

Cited by 121 publications

(121 citation statements)

References 54 publications

(71 reference statements)

Supporting

Mentioning

115

Contrasting

Order By: Relevance

“…In the context of CD8 + T cell differentiation, a shift in DNA methylation is not a straightforward phenomenon once CD8 + T cells have retained their specific memory subset. Accordingly, effector‐associated loci, such as PRF1 , have a stably unchanged DNA methylation in peripheral blood‐derived naive, T CM and T EM CD8 + T cells, even after three rounds of cell division by ex‐vivo stimulation using homeostatic cytokines IL‐7 and IL‐15 [28]. …”

Section: Discussionmentioning

confidence: 99%

Tissue-resident memory T cells are epigenetically cytotoxic with signs of exhaustion in human urinary bladder cancer

Hartana

Bergman

Broomé

et al. 2018

Clinical and Experimental Immunology

View full text Add to dashboard Cite

SummaryTissue‐resident memory T (TRM) cells are CD8+ T lymphocytes that reside in the tissues, including tumours. This T cell subset possesses a magnitude of cytotoxicity, but its epigenetic regulation has not been studied. Here, we investigate the impact of perforin DNA methylation in TRM cells and correlate it with their functional potential. Fifty‐three urothelial urinary bladder cancer (UBC) patients were recruited prospectively. The DNA methylation status of the perforin gene (PRF1) locus in TRM cells was investigated by pyrosequencing. Flow cytometry with ViSNE analysis and in‐vitro stimulation were used to evaluate TRM cell phenotypes. We discovered that tumour TRM cells have low DNA methylation in the PRF1 locus (32·9% methylation), which corresponds to increased numbers of perforin‐expressing TRM cells. Surprisingly, programmed cell death 1 (PD‐1) expression is high in tumour TRM cells, suggesting exhaustion. Following interleukin‐15 and T cell receptor stimulation, perforin and T‐bet expressions are enhanced, indicating that TRM cells from tumours are not terminally exhausted. Moreover, a high number of TRM cells infiltrating the tumours corresponds to lower tumour stage in patients. In conclusion, TRM cells from UBC tumours are epigenetically cytotoxic with signs of exhaustion. This finding identifies TRM cells as potential new targets for cancer immunotherapy.

show abstract

Section: Discussionmentioning

confidence: 99%

Tissue-resident memory T cells are epigenetically cytotoxic with signs of exhaustion in human urinary bladder cancer

Hartana

Bergman

Broomé

et al. 2018

Clinical and Experimental Immunology

View full text Add to dashboard Cite

show abstract

“…Open circles depict unmethylated CpG while filled circles depict methylated CpG. These data and analyses are representative of published data (Abdelsamed et al ., 2017; Ghoneim et al ., 2017). …”

Section: Figurementioning

confidence: 67%

“…After 7 days of culture, sort undivided and divided cell populations (third division or more) for DNA-methylation analysis as shown in Figure 1A (Abdelsmed et al ., 2017). …”

Section: Methodsmentioning

confidence: 99%

“…Below we describe an in vitro homeostatic proliferation assay that enables us to analyze mechanisms that regulate fate commitment during human memory T-cell homeostasis. We specifically describe loci-specific bisulfite-sequencing DNA-methylation analysis to examine the stability of effector DNA-methylation programs in memory CD8 T-cell subsets over several rounds of cell division (Abdelsamed et al ., 2017). …”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

In vitro Homeostatic Proliferation of Human CD8 T Cells

2017

Self Cite

View full text Add to dashboard Cite

Long-lived T-cell–mediated immunity requires persistence of memory T cells in an antigen-free environment while also maintaining a heightened capacity to recall effector functions. Such antigen-independent homeostatic proliferation is mediated in part by the common gamma-chain cytokines IL-7 and IL-15. To further explore the mechanisms governing maintenance of effector functions in long-lived memory T cells during antigen-independent proliferation, human naïve and memory CD8 T cells can be sorted from peripheral blood mononuclear cells (PBMCs), labeled with the proliferation-tracking dye carboxyfluorescein succinimidyl ester (CFSE), and then purified based on their levels of cell division. This allows investigators to assess differences in the desired molecular target in cells that have undergone cytokine-driven proliferation. We provide here a protocol for assessing epigenetic programs in divided and undivided human naïve and memory CD8 T cells following 7 days in culture with IL-7 and IL-15 to illustrate how this approach can shed light on the mechanism(s) that governs the preservation of effector functions during homeostasis of long-lived memory CD8 T cells.

show abstract

“…The number of memory T cells required for initial adoptive transfer therapy will be significantly lower than the current practice as memory cells can be primed in vivo using vaccine to regenerate CTL as needed. Current approaches to induce Tscm-like ACT include 1) Cytokines addition: IL-7, IL-15, IL-21 [70]; 2) using inhibitors for AKT,m-TORC and PI3K [71,72]; 3) activation of NOTCH [73]; 4) Weak TCR signaling during activation [74]; 5)providing additional costimulation e.g. 4-1BB, ICOS [75]; 6) altered metabolism status [76,77].…”

Section: The Influence Of Immunosuppressive Tumor Microenvironment (Tmentioning

confidence: 99%

Adoptive CD8+ T cell therapy against cancer:Challenges and opportunities

Jiang

Liu

et al. 2019

Cancer Letters

View full text Add to dashboard Cite

Human memory CD8 T cell effector potential is epigenetically preserved during in vivo homeostasis

Abstract: Abdelsamed et al. demonstrate that the poised effector potential of human memory CD8 T cells is coupled to maintenance of effector-associated DNA methylation programs during in vitro and in vivo homeostatic proliferation.

Cited by 121 publications

References 54 publications

Tissue-resident memory T cells are epigenetically cytotoxic with signs of exhaustion in human urinary bladder cancer

Tissue-resident memory T cells are epigenetically cytotoxic with signs of exhaustion in human urinary bladder cancer

In vitro Homeostatic Proliferation of Human CD8 T Cells

Adoptive CD8+ T cell therapy against cancer:Challenges and opportunities

Contact Info

Product

Resources

About