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

doi:10.1016/j.immuni.2015.02.008

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

Immunity. 2015 Mar 17;42(3):443-56. doi: 10.1016/j.immuni.2015.02.008.

Authors

Heinrich Schlums¹, Frank Cichocki², Bianca Tesi³, Jakob Theorell¹, Vivien Beziat¹, Tim D Holmes¹, Hongya Han¹, Samuel C C Chiang¹, Bree Foley⁴, Kristin Mattsson¹, Stella Larsson⁵, Marie Schaffer⁶, Karl-Johan Malmberg⁷, Hans-Gustaf Ljunggren¹, Jeffrey S Miller⁴, Yenan T Bryceson⁸

Affiliations

¹ Centre for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden.
² Centre for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden; Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota Cancer Center, Minneapolis, MN 55455, USA.
³ Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital Solna, 17164 Stockholm, Sweden; Clinical Genetics Unit, Department of Molecular Medicine and Surgery, and Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital Solna, 14186 Stockholm, Sweden.
⁴ Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota Cancer Center, Minneapolis, MN 55455, USA.
⁵ Department of Clinical Immunology and Transfusion Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden.
⁶ Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden.
⁷ Centre for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden; K.G. Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, 0310 Oslo, Norway; Department of Immunology, Institute for Cancer Research, Oslo University Hospital, 0310 Oslo, Norway.
⁸ Centre for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden; Broegelmann Research Laboratory, Department of Clinical Sciences, University of Bergen, 5021 Bergen, Norway. Electronic address: yenan.bryceson@ki.se.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptive Immunity
Antibodies / immunology*
Cell Proliferation
Cytomegalovirus / immunology
Cytomegalovirus Infections / genetics*
Cytomegalovirus Infections / immunology
Cytomegalovirus Infections / pathology
Cytomegalovirus Infections / virology
DNA Methylation
Epigenesis, Genetic / immunology*
GPI-Linked Proteins / genetics
GPI-Linked Proteins / immunology
Gene Expression Profiling
Humans
Immunophenotyping
Intracellular Signaling Peptides and Proteins / deficiency
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / immunology
Killer Cells, Natural / classification
Killer Cells, Natural / immunology*
Killer Cells, Natural / pathology
Killer Cells, Natural / virology
Kruppel-Like Transcription Factors / deficiency
Kruppel-Like Transcription Factors / genetics
Kruppel-Like Transcription Factors / immunology*
Microarray Analysis
NK Cell Lectin-Like Receptor Subfamily C / deficiency
NK Cell Lectin-Like Receptor Subfamily C / genetics
NK Cell Lectin-Like Receptor Subfamily C / immunology
Promoter Regions, Genetic
Promyelocytic Leukemia Zinc Finger Protein
Protein-Tyrosine Kinases / deficiency
Protein-Tyrosine Kinases / genetics
Protein-Tyrosine Kinases / immunology
Receptors, IgG / deficiency
Receptors, IgG / genetics
Receptors, IgG / immunology
Signal Transduction
Syk Kinase
T-Lymphocytes, Cytotoxic / immunology*
T-Lymphocytes, Cytotoxic / pathology
T-Lymphocytes, Cytotoxic / virology
Transcription Factors / deficiency
Transcription Factors / genetics
Transcription Factors / immunology

Substances

Antibodies
FCGR3B protein, human
GPI-Linked Proteins
Intracellular Signaling Peptides and Proteins
KLRC2 protein, human
Kruppel-Like Transcription Factors
NK Cell Lectin-Like Receptor Subfamily C
Promyelocytic Leukemia Zinc Finger Protein
Receptors, IgG
SH2D1B protein, human
Transcription Factors
ZBTB16 protein, human
Protein-Tyrosine Kinases
SYK protein, human
Syk Kinase

Associated data

GEO/GSE66564

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding