Epigenetic modification of the PD-1 (Pdcd1) promoter in effector CD4(+) T cells tolerized by peptide immunotherapy

Rhoanne C. McPherson; Joanne E. Konkel; Catriona T. Prendergast; John P. Thomson; Raffaele Ottaviano; Melanie D. Leech; Oliver Kay; Stephanie E. J. Zandee; Claire H. Sweenie; David C. Wraith; Richard R. Meehan; Amanda J. Drake; Stephen M. Anderton

doi:10.7554/eLife.03416

Epigenetic modification of the PD-1 (Pdcd1) promoter in effector CD4(+) T cells tolerized by peptide immunotherapy

Rhoanne C. McPherson, Joanne E. Konkel, Catriona T. Prendergast, John P. Thomson, Raffaele Ottaviano, Melanie D. Leech, Oliver Kay, Stephanie E. J. Zandee, Claire H. Sweenie, David C. Wraith, Richard R. Meehan, Amanda J. Drake, Stephen M. Anderton^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

Clinically effective antigen-based immunotherapy must silence antigen-experienced effector T cells (Teff) driving ongoing immune pathology. Using CD4(+) autoimmune Teff cells, we demonstrate that peptide immunotherapy (PIT) is strictly dependent upon sustained T cell expression of the co-inhibitory molecule PD-1. We found high levels of 5-hydroxymethylcytosine (5hmC) at the PD-1 (Pdcd1) promoter of non-tolerant T cells. 5hmC was lost in response to PIT, with DNA hypomethylation of the promoter. We identified dynamic changes in expression of the genes encoding the Ten-Eleven-Translocation (TET) proteins that are associated with the oxidative conversion 5-methylcytosine and 5hmC, during cytosine demethylation. We describe a model whereby promoter demethylation requires the co-incident expression of permissive histone modifications at the Pdcd1 promoter together with TET availability. This combination was only seen in tolerant Teff cells following PIT, but not in Teff that transiently express PD1. Epigenetic changes at the Pdcd1 locus therefore determine the tolerizing potential of TCR-ligation.

Original language	English
Number of pages	37
Journal	eLIFE
Volume	3
Early online date	29 Dec 2014
DOIs	https://doi.org/10.7554/eLife.03416
Publication status	Published - 29 Dec 2014

Keywords / Materials (for Non-textual outputs)

EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS
CHRONIC VIRAL-INFECTION
DENDRITIC CELLS
IN-VIVO
PROGRAMMED DEATH-1
CLONAL EXPANSION
PHOSPHATASE SHP2
SELECTIN LIGAND
DNA METHYLATION
TOLERANCE

Access to Document

10.7554/eLife.03416

Epigenetic modification of the PD-1 (Pdcd1) promoter in effector CD4+ T cells tolerized by peptide immunotherapy
© 2014, McPherson et al This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Final published version, 1.71 MBLicence: Creative Commons: Attribution (CC-BY)

The role of T-bet in Foxp3+ regulatory cell-mediated protection from autoimmune inflammation
Anderton, S. & O'Connor, R.
MRC
1/04/12 → 31/03/15
Project: Research
How do myelin-reactive memory T cells respond to antigen administration?
Anderton, S.
UK-based charities
1/04/09 → 31/03/12
Project: Research
Immune cell interactions in the inflammed CNS
Anderton, S. & O'Connor, R.
MRC
1/04/09 → 30/09/14
Project: Research

Cite this

McPherson, R. C., Konkel, J. E., Prendergast, C. T., Thomson, J. P., Ottaviano, R., Leech, M. D., Kay, O., Zandee, S. E. J., Sweenie, C. H., Wraith, D. C., Meehan, R. R., Drake, A. J., & Anderton, S. M. (2014). Epigenetic modification of the PD-1 (Pdcd1) promoter in effector CD4(+) T cells tolerized by peptide immunotherapy. eLIFE, 3. https://doi.org/10.7554/eLife.03416

@article{6eeef86a4b5f478a9f709ac177045ace,

title = "Epigenetic modification of the PD-1 (Pdcd1) promoter in effector CD4(+) T cells tolerized by peptide immunotherapy",

abstract = "Clinically effective antigen-based immunotherapy must silence antigen-experienced effector T cells (Teff) driving ongoing immune pathology. Using CD4(+) autoimmune Teff cells, we demonstrate that peptide immunotherapy (PIT) is strictly dependent upon sustained T cell expression of the co-inhibitory molecule PD-1. We found high levels of 5-hydroxymethylcytosine (5hmC) at the PD-1 (Pdcd1) promoter of non-tolerant T cells. 5hmC was lost in response to PIT, with DNA hypomethylation of the promoter. We identified dynamic changes in expression of the genes encoding the Ten-Eleven-Translocation (TET) proteins that are associated with the oxidative conversion 5-methylcytosine and 5hmC, during cytosine demethylation. We describe a model whereby promoter demethylation requires the co-incident expression of permissive histone modifications at the Pdcd1 promoter together with TET availability. This combination was only seen in tolerant Teff cells following PIT, but not in Teff that transiently express PD1. Epigenetic changes at the Pdcd1 locus therefore determine the tolerizing potential of TCR-ligation.",

keywords = "EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS, CHRONIC VIRAL-INFECTION, DENDRITIC CELLS, IN-VIVO, PROGRAMMED DEATH-1, CLONAL EXPANSION, PHOSPHATASE SHP2, SELECTIN LIGAND, DNA METHYLATION, TOLERANCE",

author = "McPherson, {Rhoanne C.} and Konkel, {Joanne E.} and Prendergast, {Catriona T.} and Thomson, {John P.} and Raffaele Ottaviano and Leech, {Melanie D.} and Oliver Kay and Zandee, {Stephanie E. J.} and Sweenie, {Claire H.} and Wraith, {David C.} and Meehan, {Richard R.} and Drake, {Amanda J.} and Anderton, {Stephen M.}",

year = "2014",

month = dec,

day = "29",

doi = "10.7554/eLife.03416",

language = "English",

volume = "3",

journal = "eLIFE",

issn = "2050-084X",

publisher = "ELIFE SCIENCES PUBLICATIONS LTD",

}

TY - JOUR

T1 - Epigenetic modification of the PD-1 (Pdcd1) promoter in effector CD4(+) T cells tolerized by peptide immunotherapy

AU - McPherson, Rhoanne C.

AU - Konkel, Joanne E.

AU - Prendergast, Catriona T.

AU - Thomson, John P.

AU - Ottaviano, Raffaele

AU - Leech, Melanie D.

AU - Kay, Oliver

AU - Zandee, Stephanie E. J.

AU - Sweenie, Claire H.

AU - Wraith, David C.

AU - Meehan, Richard R.

AU - Drake, Amanda J.

AU - Anderton, Stephen M.

PY - 2014/12/29

Y1 - 2014/12/29

N2 - Clinically effective antigen-based immunotherapy must silence antigen-experienced effector T cells (Teff) driving ongoing immune pathology. Using CD4(+) autoimmune Teff cells, we demonstrate that peptide immunotherapy (PIT) is strictly dependent upon sustained T cell expression of the co-inhibitory molecule PD-1. We found high levels of 5-hydroxymethylcytosine (5hmC) at the PD-1 (Pdcd1) promoter of non-tolerant T cells. 5hmC was lost in response to PIT, with DNA hypomethylation of the promoter. We identified dynamic changes in expression of the genes encoding the Ten-Eleven-Translocation (TET) proteins that are associated with the oxidative conversion 5-methylcytosine and 5hmC, during cytosine demethylation. We describe a model whereby promoter demethylation requires the co-incident expression of permissive histone modifications at the Pdcd1 promoter together with TET availability. This combination was only seen in tolerant Teff cells following PIT, but not in Teff that transiently express PD1. Epigenetic changes at the Pdcd1 locus therefore determine the tolerizing potential of TCR-ligation.

AB - Clinically effective antigen-based immunotherapy must silence antigen-experienced effector T cells (Teff) driving ongoing immune pathology. Using CD4(+) autoimmune Teff cells, we demonstrate that peptide immunotherapy (PIT) is strictly dependent upon sustained T cell expression of the co-inhibitory molecule PD-1. We found high levels of 5-hydroxymethylcytosine (5hmC) at the PD-1 (Pdcd1) promoter of non-tolerant T cells. 5hmC was lost in response to PIT, with DNA hypomethylation of the promoter. We identified dynamic changes in expression of the genes encoding the Ten-Eleven-Translocation (TET) proteins that are associated with the oxidative conversion 5-methylcytosine and 5hmC, during cytosine demethylation. We describe a model whereby promoter demethylation requires the co-incident expression of permissive histone modifications at the Pdcd1 promoter together with TET availability. This combination was only seen in tolerant Teff cells following PIT, but not in Teff that transiently express PD1. Epigenetic changes at the Pdcd1 locus therefore determine the tolerizing potential of TCR-ligation.

KW - EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS

KW - CHRONIC VIRAL-INFECTION

KW - DENDRITIC CELLS

KW - IN-VIVO

KW - PROGRAMMED DEATH-1

KW - CLONAL EXPANSION

KW - PHOSPHATASE SHP2

KW - SELECTIN LIGAND

KW - DNA METHYLATION

KW - TOLERANCE

U2 - 10.7554/eLife.03416

DO - 10.7554/eLife.03416

M3 - Article

SN - 2050-084X

VL - 3

JO - eLIFE

JF - eLIFE

ER -

Epigenetic modification of the PD-1 (Pdcd1) promoter in effector CD4(+) T cells tolerized by peptide immunotherapy

Abstract / Description of output

Keywords / Materials (for Non-textual outputs)

Access to Document

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Projects

The role of T-bet in Foxp3+ regulatory cell-mediated protection from autoimmune inflammation

How do myelin-reactive memory T cells respond to antigen administration?

Immune cell interactions in the inflammed CNS

Cite this