Epigenetic modification of the PD-1 (Pdcd1) promoter in effector CD4(+) T cells tolerized by peptide immunotherapy
ELIFE
Authors: McPherson, Rhoanne C.; Konkel, Joanne E.; Prendergast, Catriona T.; Thomson, John P.; Ottaviano, Raffaele; Leech, Melanie D.; Kay, Oliver; Zandee, Stephanie E. J.; Sweenie, Claire H.; Wraith, David C.; Meehan, Richard R.; Drake, Amanda J.; Anderton, Stephen M.
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.
PD-1 deficiency augments bone marrow failure in a minor-histocompatibility antigen mismatch lymphocyte infusion model
EXPERIMENTAL HEMATOLOGY
Authors: Hollinger, Maile K.; Giudice, Valentina; Cummings, Nicole A.; Rivell, Guillermo; Zhang, Hansheng; Kajigaya, Sachiko; Keyvanfar, Keyvan; Chen, Jichun; Feng, Xingmin; Young, Neal S.
Abstract
Although PD-1 blockade has revolutionized cancer immunotherapy, immune-related adverse events (irAEs) present life -threatening complications. Recent reports of aplastic anemia (AA) as irAEs implicate PD-1/PD-L1 as important in preventing immune-mediated destruction of the hematopoietic niche. Infusion of PD-1-deficient (PD-1 knockout [KO]) lymph node (LN) cells into minor-antigen mismatched mice resulted in early mortality, as well as more severe bone marrow (BM) hypoplasia, anemia, and BM microarchitecture disruption in PD-1 KO LN-infused mice relative to mice that received B6 LN cell infusion. Mice that received PD-1 KO LN cells had more CD8(+) T-cell infiltration of the BM and greater expansion of H60-specific CD8(+) T cells than did their B6 LN-infused counterparts. In the spleen, CD8+ T cells were skewed to an effector memory phenotype, suggesting accelerated differentiation of PD-1 KO T cells. Our data suggest that PD-1 dysregulation has a role in murine BM failure and vigilance in irAE monitoring may be desirable to treat early AA and related cytopenias. Published by Elsevier Inc. on behalf of ISEH - Society for Hematology and Stem Cells.
COA
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