DNA accessibility in reactive and non-reactive CMV specific CD8+ lymphocytes

Poor immune reconstitution following haematopoietic stem cell transplantation (HSCT) can cause unwanted and harmful sequelae in recipients with chronic cytomegalovirus (CMV) infection. To understand the molecular mechanisms underlying poor reconstitution, we profiled the transcriptome-chromatin accessibility landscape of CMV-specific CD8+ memory lymphocytes from HCST recipients with different reconstitution efficiencies. Although the transcriptional and epigenomic signatures in non-reactive lymphocytes were not naïve or classic ‘exhaustion’ profiles, some gene expression was common to lymphocytes from other non-resolving infections. Reactive lymphocytes expressed higher levels of interferon/defence response and cell cycle genes in an interconnected network involving PI3KCG, STAT5B, NFAT, RBPJ, and NR3C1, increasing chromatin accessibility at the enhancer regions of immune and T cell receptor signalling pathway genes. We propose that increased HDAC6 expression in non-reactive lymphocytes decreases accessibility at particular enhancers including PI3KCG. Non-reactive cells also expressed higher levels of EGR and KLF factors that, along with lower expression of JARID2, maintained higher accessibility at promoter and CpG-rich regions of genes associated with apoptosis. Together, transcription factors and chromatin modulators create a different chromatin accessibility landscape in reactive and non-reactive cells that not only affects immediate gene expression but differentially primes the cells for responses to additional signals.