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

• Published in: The Journal of clinical investigation 2014-12, Vol.124 (12), p.5305-5316
• Main Authors: Rölle, Alexander, Pollmann, Julia, Ewen, Eva-Maria, Le, Vu Thuy Khanh, Halenius, Anne, Hengel, Hartmut, Cerwenka, Adelheid
• Format: Article
• Language: English
• Subjects: Biomedical research; Blood & organ donations; Cloning; Cytomegalovirus; Cytomegalovirus - immunology; Cytomegalovirus Infections - immunology; Cytomegalovirus Infections - pathology; Expansion; Female; Histocompatibility Antigens Class I - immunology; HLA-E Antigens; Human cytomegalovirus; Humans; Immune system; Immunity, Cellular; Infections; Interleukin-12 - immunology; Interleukin-2 Receptor alpha Subunit - immunology; Killer Cells, Natural - immunology; Killer Cells, Natural - pathology; Ligands; Lipopolysaccharide Receptors - immunology; Male; Monocytes - immunology; Monocytes - pathology; NK Cell Lectin-Like Receptor Subfamily C - immunology; NK Cell Lectin-Like Receptor Subfamily D - immunology; Statistical analysis; Viral infections
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci77440

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.