Nuclear PKC-θ facilitates rapid transcriptional responses in human memory CD4+ T cells via p65 and H2B phosphorylation

Abstract

Memory T cells are characterised by their rapid transcriptional programs upon re-stimulation. This transcriptional memory (TM) response is facilitated by permissive chromatin but exactly how the permissive epigenetic landscape in memory T cells integrates incoming stimulatory signals remains poorly understood. By genome-wide ChIP-sequencing ex vivo human CD4+ T cells, we show that the signaling enzyme, protein kinase C-theta (PKC-θ) directly relays stimulatory signals to chromatin by binding to TM-responsive genes to induce transcriptional activation. Flanked by permissive histone modifications, these PKC-enriched regions are significantly enriched with NF-κB motifs in ex vivo bulk and vaccinia-responsive human memory CD4+ T cells. Within the nucleus, PKC-θ catalytic activity maintains p65 Ser536 phosphorylation and can directly influence chromatin accessibility at TM genes by regulating H2B deposition via Ser32 phosphorylation. Furthermore, using a cytoplasm-restricted PKC-θ mutant, we highlight chromatin-anchored PKC-θ integrates activating signals at the chromatin template to elicit transcriptional memory responses in human memory T cells.