Cytomegalovirus infection drives adaptive epigenetic diversification of NK cells with altered signaling and effector function

Heinrich Schlums, Frank Cichocki, Bianca Tesi, Jakob Theorell, Vivien Beziat, Tim D Holmes, Hongya Han, Samuel C C Chiang, Bree Foley, Kristin Mattsson, Stella Larsson, Marie Schaffer, Karl-Johan Malmberg, Hans-Gustaf Ljunggren, Jeffrey S Miller, Yenan T Bryceson

Research output: Contribution to journalArticlepeer-review

459 Citations (Scopus)

Abstract

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 hypermethylation. 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.

Original languageEnglish
Pages (from-to)443-56
Number of pages14
JournalImmunity
Volume42
Issue number3
DOIs
Publication statusPublished - 17 Mar 2015
Externally publishedYes

Fingerprint

Dive into the research topics of 'Cytomegalovirus infection drives adaptive epigenetic diversification of NK cells with altered signaling and effector function'. Together they form a unique fingerprint.

Cite this