CXCR5gene expression in human lymph node CD8⁺T cells is regulated by DNA methylation and nucleosomal occupancy

Abstract

CD8 + T cells play an important role in viral and tumour control. However, in human lymph nodes (LNs), only a small subset of CD8 + T cells called follicular CD8 + T cells (fCD8s) expresses CXCR5, the chemokine receptor required for cell migration into B cell follicles, thought to promote immune evasion. Here we obtained LNs from HIV infected persons to investigate regulation of CXCR5 expression in lymphoid CD8 + T cells, and compared this to the more abundant CXCR5 expressing T follicular CD4 + helper cells (GCTfh). Our results show that DNA hypermethylation and closed chromatin at the transcriptional start site (TSS) prevent CXCR5 expression in non-fCD8s. We also found that greater nucleosomal density at the CXCR5 TSS could be responsible for reduced CXCR5 expression in fCD8s relative to GCTfh. Together, these data provide critical insights into both the underlying molecular mechanisms that repress CXCR5 expression in non-fCD8s and the plausible mechanism responsible for the low CXCR5 expression in fCD8s, with implications for HIV cure strategies.