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

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Abstract

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.

Authors

Alexander Rölle, Julia Pollmann, Eva-Maria Ewen, Vu Thuy Khanh Le, Anne Halenius, Hartmut Hengel, Adelheid Cerwenka