IL-12-producing monocytes and HLA-E control HCMV-driven NKG2C+ NK cell expansion

J Clin Invest. 2014 Dec;124(12):5305-16. doi: 10.1172/JCI77440. Epub 2014 Nov 10.


Human cytomegalovirus (HCMV) infection is the most common cause of congenital viral infections and a major source of morbidity and mortality after organ transplantation. NK cells are pivotal effector cells in the innate defense against CMV. Recently, hallmarks of adaptive responses, such as memory-like features, have been recognized in NK cells. HCMV infection elicits the expansion of an NK cell subset carrying an activating receptor heterodimer, comprising CD94 and NKG2C (CD94/NKG2C), a response that resembles the clonal expansion of adaptive immune cells. Here, we determined that expansion of this NKG2C(+) subset and general NK cell recovery rely on signals derived from CD14(+) monocytes. In a coculture system, a subset of CD14(+) cells with inflammatory monocyte features produced IL-12 in response to HCMV-infected fibroblasts, and neutralization of IL-12 in this model substantially reduced CD25 upregulation and NKG2C(+) subset expansion. Finally, blockade of CD94/NKG2C on NK cells or silencing of the cognate ligand HLA-E in infected fibroblasts greatly impaired expansion of NKG2C(+) NK cells. Together, our results reveal that IL-12, CD14(+) cells, and the CD94/NKG2C/HLA-E axis are critical for the expansion of NKG2C(+) NK cells in response to HCMV infection. Moreover, strategies targeting the NKG2C(+) NK cell subset have the potential to be exploited in NK cell-based intervention strategies against viral infections and cancer.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cytomegalovirus / immunology*
  • Cytomegalovirus Infections / immunology*
  • Cytomegalovirus Infections / pathology
  • Female
  • Histocompatibility Antigens Class I / immunology*
  • Humans
  • Immunity, Cellular
  • Interleukin-12 / immunology*
  • Interleukin-2 Receptor alpha Subunit / immunology
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / pathology
  • Lipopolysaccharide Receptors / immunology
  • Male
  • Monocytes / immunology*
  • Monocytes / pathology
  • NK Cell Lectin-Like Receptor Subfamily C / immunology*
  • NK Cell Lectin-Like Receptor Subfamily D / immunology


  • HLA-E antigen
  • Histocompatibility Antigens Class I
  • IL2RA protein, human
  • Interleukin-2 Receptor alpha Subunit
  • KLRC2 protein, human
  • KLRD1 protein, human
  • Lipopolysaccharide Receptors
  • NK Cell Lectin-Like Receptor Subfamily C
  • NK Cell Lectin-Like Receptor Subfamily D
  • Interleukin-12