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Closed chromatin of the CXCR5 gene due to DNA hypermethylation limits trafficking potential of CD8+ T cells into B cell follicles during HIV-1 clade C infection

ABSTRACT: CD8+ T cells play an important role in HIV control. However, in human lymph nodes (LNs), only a small subset of CD8+ T cells expresses CXCR5, the chemokine receptor required for cell migration into B cell follicles, which are major sanctuaries for HIV persistence in individuals on therapy. Here, we investigate the impact of HIV infection on follicular CD8+ T cells (fCD8s) frequencies, trafficking pattern and CXCR5 regulation. We show that, although HIV infection results in a marginal increase of fCD8s in LN, the majority of HIV-specific CD8+ T cells are CXCR5 negative (non-fCD8s) (p<0.003). Mechanistic investigations using ATAC-seq showed that non-fCD8s have closed chromatin at the CXCR5 transcriptional start site (TSS). DNA bisulfite sequencing identified DNA hypermethylation at the CXCR5 TSS as the most probable cause of closed chromatin. Transcriptional factor footprints analysis revealed enrichment of transforming growth factors (TGFs) at the TSS of fCD8s. In40 vitro stimulation of non-fCD8s with recombinant TGF-β resulted in significant increase in CXCR5 expression (fCD8s). Thus, this study identifies TGF-β signaling as a viable strategy for increasing fCD8s frequencies in follicular areas of the LN where they are needed to eliminate HIV infected cells, with implications for HIV cure strategies. ~

ORGANISM(S): Homo sapiens

PROVIDER: GSE180532 | GEO | 2022/03/30

REPOSITORIES: GEO

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