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 PD-1. Epigenetic changes at the Pdcd1 locus therefore determine the tolerizing potential of TCR-ligation.
Highlights
Antigen-based immunotherapy remains the ‘holy grail’ of immune tolerance because it should target only those pathogenic lymphocytes driving autoimmune, allergic, or alloreactive immunopathology, whilst leaving beneficial immune surveillance unaltered
We concluded from these initial studies that a single exposure to the myelin basic protein (MBP) peptide was sufficient for successful peptide immunotherapy (PIT), without enhanced induction of cell death, or establishment of Treg-mediated suppression, but rather an intrinsic unresponsiveness in the persisting Tg4 cells
Our data provide key insights into the mechanisms of T effector (Teff) cell unresponsiveness induced by PIT, which are pertinent to its clinical translation
Summary
Antigen-based immunotherapy remains the ‘holy grail’ of immune tolerance because it should target only those pathogenic lymphocytes driving autoimmune, allergic, or alloreactive immunopathology, whilst leaving beneficial immune surveillance unaltered. Peptide immunotherapy (PIT) is the subject of clinical trials in autoimmune and allergic disease (Larche and Wraith, 2005; Larché, 2007). Despite this the molecular basis for effects of PIT, on T effector (Teff) cells, which is the clinical imperative, remains to be fully understood. Signalling through PD-1 upon TCR stimulation has been shown to inhibit proliferation and the production of IL-2 and effector cytokines by T cells
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