Impaired Memory CD8 T Cell Development in the Absence of Methyl-CpG-Binding Domain Protein 2

Abstract

Intracellular differentiation events that determine which cells develop into memory CD8 T cells are currently incompletely understood. Methyl-CpG-binding domain protein 2 (MBD2) is a transcriptional repressor that binds to methylated DNA and mediates the biological consequences of epigenetic gene methylation. The role of MBD2 during the differentiation of naive CD8 T cells into effector and memory cells was determined following acute infection of MBD2-deficient mice with lymphocytic choriomeningitis virus. Despite rapid viral clearance and an efficient primary effector CD8 T cell response, reduced numbers of Ag-specific memory CD8 T cells were observed. Importantly, the appearance of precursor memory cells (IL-7Rαhigh) was delayed. The remaining MBD2−/− memory cells were not fully protective during rechallenge, and memory cell characteristics were altered with regard to surface markers (IL-7Rα, KLRG-1, CD27, and others) and cytokine production. The defect was CD8 T cell intrinsic, because memory cell development was also delayed when MBD2−/− CD8 T cells were adoptively transferred into SCID mice. These data demonstrate that MBD2 is a previously unrecognized intracellular factor required for the efficient generation of protective memory CD8 T cells.

Defining CD4 T Cell Memory by the Epigenetic Landscape of CpG DNA Methylation

“…While we are unable to address the question of demethylation of the IFNG promoter as the targeted regions did not reach sufficient read depth in our analysis, high depth analysis of unstimulated naïve and memory cells from two donors showed that CD4 memory T cells are hypomethylated compared to naïve, suggesting that the demethylation of the IFNG promoter upon differentiation into effector cells is maintained following development of a CD4 memory phenotype. Interestingly, studies in murine CD8 T cells have demonstrated that the IFNG promoter and enhancer is hypermethylated in memory cells compared to effector cells, but is rapidly demethylated in response to antigenic stimulation (42, 43). Such differences between epigenetic regulation of single genes in CD4 and CD8 T cells highlights the importance of cell specific transcriptional regulation.…”

Genetic, Epigenetic and Pharmacogenetic Aspects of Psoriasis and Psoriatic Arthritis

“…RUNX3, TNFRSF9, and MBD2 encode proteins involved in the generation of CD8 T cells. [53][54][55] Similarly, ETS1, IRF4, TAGAP, and B3GNT2 encode proteins involved in the activation and differentiation of CD8 T cells. 53,56,57 That ERAP1 codes for a protein that trims peptides in the endoplasmic reticulum before their MHC class I presentation, 58 and that it interacts with HLA-C indicates that this gene is important for antigen presentation.…”

Coordinated Changes in DNA Methylation in Antigen-Specific Memory CD4 T Cells

“…A limiting DNA methylation affects the proliferative potential of Ag-specific CD8 + T cells with moderate effects on their differentiation to effector and memory CD8 + T cells (20). Additionally, methyl-CpG-binding domain protein 2-deficient mice display reduced memory CD8 + T cell differentiation following acute viral infection (21).…”