Epigenetic Modification and Antibody-Dependent Expansion of Memory-like NK Cells in Human Cytomegalovirus-Infected Individuals

Abstract

Summary Long-lived ‘memory-like’ NK cells have been identified in individuals infected by human cytomegalovirus (HCMV), but little is known about how the memory-like NK cell pool is formed. Here, we have shown that HCMV-infected individuals have several distinct subsets of memory-like NK cells that are often deficient for multiple transcription factors and signaling proteins, including tyrosine kinase SYK, for which the reduced expression was stable over time and correlated with epigenetic modification of the gene promoter. Deficient expression of these proteins was largely confined to the recently discovered FcRγ-deficient NK cells that display enhanced antibody-dependent functional activity. Importantly, FcRγ-deficient NK cells exhibited robust preferential expansion in response to virus-infected cells (both HCMV and influenza) in an antibody-dependent manner. These findings suggest that the memory-like NK cell pool is shaped and maintained by a mechanism that involves both epigenetic modification of gene expression and antibody-dependent expansion.

Sweet Is the Memory of Past Troubles: NK Cells Remember

“…These NK cells express lower levels-both transcripts and cell surface protein-of ITGA6, SIGLEC-7, CD7, PECAM1, and TIM-3, while ILT2, CD2, and FAS are expressed at higher levels (Lee et al 2015). Expression of Syk is also variable; lack of Syk is associated with CMV seropositivity and is mostly observed in the FcεRIγ neg NK cell subset (Lee et al 2015). Deficiencies in the expression of the transcription factors PLZF and DAB2 and the EAT-2 adapter protein also identify these FcεRIγ neg memory-like NK cells (Lee et al 2015;Schlums et al 2015), while expression of IKZF2 is variable.…”

“…Lack of FcεRIγ by these NK cells is associated with CD94-NKG2C and CD57 expression, although there are also CD94-NKG2C − NK cells that are FcεRIγ neg . Lee et al (2015) and Schlums et al (2015) have shown that these FcεRIγ neg memory-like NK cells also possess distinct transcription factors and signaling proteins, as well as distinct epigenetic profiles. These NK cells express lower levels-both transcripts and cell surface protein-of ITGA6, SIGLEC-7, CD7, PECAM1, and TIM-3, while ILT2, CD2, and FAS are expressed at higher levels (Lee et al 2015).…”

“…Lee et al (2015) and Schlums et al (2015) have shown that these FcεRIγ neg memory-like NK cells also possess distinct transcription factors and signaling proteins, as well as distinct epigenetic profiles. These NK cells express lower levels-both transcripts and cell surface protein-of ITGA6, SIGLEC-7, CD7, PECAM1, and TIM-3, while ILT2, CD2, and FAS are expressed at higher levels (Lee et al 2015). Expression of Syk is also variable; lack of Syk is associated with CMV seropositivity and is mostly observed in the FcεRIγ neg NK cell subset (Lee et al 2015).…”

“…Expression of Syk is also variable; lack of Syk is associated with CMV seropositivity and is mostly observed in the FcεRIγ neg NK cell subset (Lee et al 2015). Deficiencies in the expression of the transcription factors PLZF and DAB2 and the EAT-2 adapter protein also identify these FcεRIγ neg memory-like NK cells (Lee et al 2015;Schlums et al 2015), while expression of IKZF2 is variable. Hypermethylation at the promoter of several of these genes likely drives the phenotype observed and imparts stability to the subset (Lee et al 2015;Schlums et al 2015).…”

“…Deficiencies in the expression of the transcription factors PLZF and DAB2 and the EAT-2 adapter protein also identify these FcεRIγ neg memory-like NK cells (Lee et al 2015;Schlums et al 2015), while expression of IKZF2 is variable. Hypermethylation at the promoter of several of these genes likely drives the phenotype observed and imparts stability to the subset (Lee et al 2015;Schlums et al 2015). These FcεRIγ neg memory-like NK cells exhibit distinct effector function from "conventional" NK cells and epigenetically closely resemble their CD8 + cytotoxic T cell counterparts (Lee et al 2015;Schlums et al 2015).…”