Cytomegalovirus Infection Drives Adaptive Epigenetic Diversification of NK Cells with Altered Signaling and Effector Function

Abstract

SUMMARY The mechanisms underlying human natural killer (NK) cell phenotypic and functional heterogeneity are unknown. Here, we describe the emergence of diverse subsets of human NK cells selectively lacking expression of signaling proteins after human cytomegalovirus (HCMV) infection. The absence of B and myeloid cell-related signaling protein expression in these NK cell subsets correlated with promoter DNA hyperme-thylation. Genome-wide DNA methylation patterns were strikingly similar between HCMV-associated adaptive NK cells and cytotoxic effector T cells but differed from those of canonical NK cells. Functional interrogation demonstrated altered cytokine responsiveness in adaptive NK cells that was linked to reduced expression of the transcription factor PLZF. Furthermore, subsets of adaptive NK cells demonstrated significantly reduced functional responses to activated autologous T cells. The present results uncover a spectrum of epigenetically unique adaptive NK cell subsets that diversify in response to viral infection and have distinct functional capabilities compared to canonical NK cell subsets.

Innate‐like CD8+ T‐cells and NK cells: converging functions and phenotypes

“…Furthermore, newly described murine innate T‐cells such as the PLZF+ ROR γ t+ natural Th17 cells96 and PLZF+ T‐CD4 T‐cells97 also express PLZF, and are highly responsive to cytokines. CMV‐specific terminally differentiated NK cells, or ‘adaptive’ NK cells, have extensively downregulated PLZF expression, due to hypermethylation of the ZBTB16 intronic sequence 98. PLZF was shown to directly bind the promoters of genes encoding signalling adaptor molecules, such as the SAP family receptor adaptor molecule EAT‐2, as well as CD161, IL‐12R and IL‐18R 98.…”

“…CMV‐specific terminally differentiated NK cells, or ‘adaptive’ NK cells, have extensively downregulated PLZF expression, due to hypermethylation of the ZBTB16 intronic sequence 98. PLZF was shown to directly bind the promoters of genes encoding signalling adaptor molecules, such as the SAP family receptor adaptor molecule EAT‐2, as well as CD161, IL‐12R and IL‐18R 98. The regulation of signalling adaptor molecules by PLZF not only affects cytokine responsiveness, but also responsiveness to receptor stimulation, as adaptive NK cells show a heightened ability to respond to ligation of receptors such as CD16 and NKG2C,70, 98 while NK cells from a PLZF‐deficient patient showed increased responsiveness of activating receptor ligation 99.…”

“…In particular, many of the effector functions of innate‐like T‐cells can be shared with CD56 bright NK cells. Furthermore, terminally differentiated/adaptive NK cells have been shown to have epigenetic modifications resembling memory CD8+ T‐cells, particularly those affecting the expression of PLZF, IFN γ , cytokine receptors and signalling proteins 98, 139. Thus, comparison of the epigenetic signature between immature NK cells and innate‐like T‐cells may also reveal important similarities associated with their innate programming, such as the expression of other members of the BTB‐ZF protein family.…”

Des cellules NK mémoire découvertes chez les primates

“…[10]. Dans des souris déficientes pour l'IFNγ, les monocytes/macrophages ne sont plus activés après vaccination et le vaccin perd une grande partie de son efficacité puisqu'il ne provoque plus de régression.…”

“…Sont-elles vraiment efficaces dans la réponse antivirale ? Certaines données suggèrent notamment qu'elles pourraient avoir une fonction diminuée [10] …”