title: Cytomegalovirus infection drives adaptive epigenetic diversification of NK cells with altered signaling and effector function.
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.
authors.affiliation: Centre for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Schlums
authors.affiliation: 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.
authors.forename: Frank
authors.initials: F
authors.lastname: Cichocki
authors.affiliation: 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.
authors.forename: Bianca
authors.initials: B
authors.lastname: Tesi
authors.affiliation: Centre for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden.
authors.forename: Jakob
authors.initials: J
authors.lastname: Theorell
authors.affiliation: Centre for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden.
authors.forename: Vivien
authors.initials: V
authors.lastname: Beziat
authors.affiliation: Centre for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden.
authors.forename: Tim D
authors.initials: TD
authors.lastname: Holmes
authors.affiliation: Centre for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden.
authors.forename: Hongya
authors.initials: H
authors.lastname: Han
authors.affiliation: Centre for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden.
authors.forename: Samuel C C
authors.initials: SC
authors.lastname: Chiang
authors.affiliation: Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota Cancer Center, Minneapolis, MN 55455, USA.
authors.forename: Bree
authors.initials: B
authors.lastname: Foley
authors.affiliation: Centre for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden.
authors.forename: Kristin
authors.initials: K
authors.lastname: Mattsson
authors.affiliation: Department of Clinical Immunology and Transfusion Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden.
authors.forename: Stella
authors.initials: S
authors.lastname: Larsson
authors.affiliation: Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Schaffer
authors.affiliation: 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.
authors.forename: Karl-Johan
authors.initials: KJ
authors.lastname: Malmberg
authors.affiliation: Centre for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden.
authors.forename: Hans-Gustaf
authors.initials: HG
authors.lastname: Ljunggren
authors.affiliation: Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota Cancer Center, Minneapolis, MN 55455, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Miller
authors.affiliation: 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.
authors.forename: Yenan T
authors.initials: YT
authors.lastname: Bryceson
mesh_terms: D056704:Adaptive Immunity; D000906:Antibodies / Q000276:immunology*; D049109:Cell Proliferation; D003587:Cytomegalovirus / Q000276:immunology; D003586:Cytomegalovirus Infections / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000821:virology; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000276:immunology*; D058851:GPI-Linked Proteins / Q000235:genetics / Q000276:immunology; D020869:Gene Expression Profiling; D006801:Humans; D016130:Immunophenotyping; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D007694:Killer Cells, Natural / Q000145:classification / Q000276:immunology* / Q000473:pathology / Q000821:virology; D051741:Kruppel-Like Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D046228:Microarray Analysis; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D011401:Promoter Regions, Genetic; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D017452:Receptors, IgG / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D000072377:Syk Kinase; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000473:pathology / Q000821:virology; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000276:immunology
chemical_list: D000906:Antibodies; C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; D047908:Intracellular Signaling Peptides and Proteins; C527059:KLRC2 protein, human; D051741:Kruppel-Like Transcription Factors; D055654:NK Cell Lectin-Like Receptor Subfamily C; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D017452:Receptors, IgG; C103572:SH2D1B protein, human; D014157:Transcription Factors; C092037:ZBTB16 protein, human; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase