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IL-12–producing monocytes and HLA-E control HCMV-driven NKG2C+ NK cell expansion
Alexander Rölle, … , Hartmut Hengel, Adelheid Cerwenka
Alexander Rölle, … , Hartmut Hengel, Adelheid Cerwenka
Published November 10, 2014
Citation Information: J Clin Invest. 2014;124(12):5305-5316. https://doi.org/10.1172/JCI77440.
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Research Article Immunology

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

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Figure 7

Blockade of CD94 or NKG2C reduces expansion of NKG2C+ NK cells in response to HCMV-infected fibroblasts.

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Blockade of CD94 or NKG2C reduces expansion of NKG2C+ NK cells in respon...
(A) Fibroblasts were stained with anti–HLA-E mAb or isotype control at the indicated time points before and after infection. (B) PBMCs were cultured with uninfected or AD169-infected fibroblasts in the presence of anti-CD94 F(ab)2 fragments or anti-NKG2C mAb or respective isotype controls. At the end of the coculture, cells were stained for NKp46, NKG2C, and CD3 and analyzed by flow cytometry. Dot plots were gated on live CD3– cells (1 representative donor out of 4 is depicted). Numbers indicate the percentages of NKG2C+ cells among all NKp46+ cells. (C) Summary of cocultures with anti-CD94 F(ab)2 fragments or (D) anti-NKG2C mAbs (paired t test: *P = 0.0314, n = 3 in C; *P = 0.0311, n = 4 in D; error bars indicate ± SEM) is shown. Plotted is the fold increase of percentage of NKG2C+NKp46+CD3– cells in infected versus uninfected cocultures.
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