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

Immunity. 2015 Mar 17;42(3):431-42. doi: 10.1016/j.immuni.2015.02.013.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Immunologic Memory*
  • 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
  • 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
  • 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

Substances

  • Antibodies
  • FCGR3B protein, human
  • GPI-Linked Proteins
  • Intracellular Signaling Peptides and Proteins
  • KLRC2 protein, human
  • NK Cell Lectin-Like Receptor Subfamily C
  • Receptors, IgG
  • Protein-Tyrosine Kinases
  • SYK protein, human
  • Syk Kinase

Associated data

  • GEO/GSE66124