PD-1 dependent exhaustion of autoaggressive effector T cells following tolerogenic peptide administration
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1
University of Edinburgh, MRC Centre for Inflammation Research, United Kingdom
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2
University of Edinburgh, MRC Human Genetics Unit, United Kingdom
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3
University of Edinburgh, Centre for Cardiovascular Sciences, United Kingdom
The clinical requirement for antigen-based therapy is to target and switch-off the activated antigen-experienced T cells involved in ongoing disease pathogenesis. Various experimental models of both autoimmune and allergic disease have demonstrated that prophylactic administration of soluble auto-antigenic peptides can be effective at inducing tolerance in naïve antigen-reactive T cells and protecting from subsequent disease induction. However, antigen-experienced T cells possess distinct activation requirements to those of naïve T cells and there exists the potential for soluble peptide administration to enhance activation of effector T cells and exacerbate ongoing disease. Using traceable TCR transgenic T cells in a model of experimental autoimmune encephalomyelitis (EAE) we demonstrate that tolerogenic peptide administration does not result in the deletion of antigen-experienced effector T cells (Teff). Despite the continued presence of the antigen-reactive Teff cells, these cells were no longer pathogenic and were unable to drive CNS autoimmune disease. Phenotypic analysis of the Teff cells following infusion of soluble peptide revealed a lack of IL-2 and effector cytokine production and high level expression of the co-inhibitory molecule PD-1. PD-1 expression was maintained for at least 16 days following peptide treatment and was required for the induction of tolerance in Teff cells, as PD-1 deficient T cells retained the ability to induce EAE following peptide treatment. Furthermore, epigenetic modifications were detected within the PD-1 promoter of Teff cells post-peptide administration, which may provide a potential mechanism for the long-term expression of this co-inhibitory molecule and the enduring tolerant phenotype observed in these cells.
Acknowledgements
This work was supported by grants from the MRC, The MS Scoiety and the Wellcome Trust.
Keywords:
T cells,
tolerance,
Autoimmunity,
PD-1,
Co-inhibition,
Epigenetic regulation,
EAE/MS
Conference:
15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013.
Presentation Type:
Abstract
Topic:
Adaptive Immunity
Citation:
Mcpherson
RC,
Konkel
JE,
Leech
MD,
Thomson
JP,
Ottaviano
R,
Meehan
RR,
Drake
AJ and
Anderton
SM
(2013). PD-1 dependent exhaustion of autoaggressive effector T cells following tolerogenic peptide administration.
Front. Immunol.
Conference Abstract:
15th International Congress of Immunology (ICI).
doi: 10.3389/conf.fimmu.2013.02.00961
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Received:
25 Jun 2013;
Published Online:
22 Aug 2013.
*
Correspondence:
Dr. Rhoanne C Mcpherson, University of Edinburgh, MRC Centre for Inflammation Research, Edinburgh, United Kingdom, r.mcpherson@ed.ac.uk