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-7Ralphahigh) 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-7Ralpha, 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.