IL-12-producing monocytes and HLA-E control HCMV-driven NKG2C+ NK cell expansion.
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.
Alexander
A
Rölle
Julia
J
Pollmann
Eva-Maria
EM
Ewen
Vu Thuy Khanh
VT
Le
Anne
A
Halenius
Hartmut
H
Hengel
Adelheid
A
Cerwenka
D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000276:immunology* / Q000473:pathology; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular; D018664:Interleukin-12 / Q000276:immunology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000473:pathology; D018950:Lipopolysaccharide Receptors / Q000276:immunology; D008297:Male; D009000:Monocytes / Q000276:immunology* / Q000473:pathology; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000276:immunology*; D051920:NK Cell Lectin-Like Receptor Subfamily D / Q000276:immunology; D000097625:HLA-E Antigens
D015395:Histocompatibility Antigens Class I; D018664:Interleukin-12; D053645:Interleukin-2 Receptor alpha Subunit; D018950:Lipopolysaccharide Receptors; D055654:NK Cell Lectin-Like Receptor Subfamily C; D051920:NK Cell Lectin-Like Receptor Subfamily D; D000097625:HLA-E Antigens; C508017:IL2RA protein, human; C527059:KLRC2 protein, human; C497869:KLRD1 protein, human