Cytomegalovirus Infection Drives Adaptive Epigenetic Diversification of NK Cells with Altered Signaling and Effector Function

By Heinrich Schlums, Frank Cichocki, B. Tesi, J. Theorell, V. Béziat, T. D. Holmes, Hongya Han, S. Chiang, B. Foley, Kristin Mattsson and 6 more. Immunity, 2015

708 citations recorded by the source corpus.

SUMMARY The mechanisms underlying human natural killer (NK) cell phenotypic and functional heterogeneity are unknown. Here, we describe the emergence of diverse subsets of human NK cells selectively lacking expression of signaling proteins after human cytomegalovirus (HCMV) infection. The absence of B and myeloid cell-related signaling protein expression in these NK cell subsets correlated with promoter DNA hyperme-thylation. Genome-wide DNA methylation patterns were strikingly similar between HCMV-associated adaptive NK cells and cytotoxic effector T cells but differed from those of canonical NK cells. Functional interrogation demonstrated altered cytokine responsiveness in adaptive NK cells that was linked to reduced expression of the transcription factor PLZF. Furthermore, subsets of adaptive NK cells demonstrated significantly reduced functional responses to activated autologous T cells. The present results uncover a spectrum of epigenetically unique adaptive NK cell subsets that diversify in response to viral infection and have distinct functional capabilities compared to canonical NK cell subsets.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/e044fc0711a31c6312f86aa22e2d7e9840e13923

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Citations in the corpus

• Integrated analysis of multimodal single-cell data (2020, positive): “This expression pattern is consistent with the development of ‘‘adaptive’’ or ‘‘memory-like’’ NK cells observed in CMV seropositive individuals (Lee et al., 2015; Schlums et al., 2015).”
• The broad spectrum of human natural killer cell diversity (2017, background): “…of adaptive NK cells is an ongoing question within the field, with multiple studies indicating similar or reduced CD107a degranulation as compared to cNK cells following CD16 ligation or stimulation with antibody-coated tumor targets (Hwang et al., 2012; Lee et al., 2015; Schlums et al., 2015).”
• Trained immunity: a program of innate immune memory in health and disease (2016, background): “Subsequently, the capacity of these adaptive NK cells to secrete cytokines was modulated and this was dependent on the transcription factor promyelocytic leukemia zinc finger (PLZF) (34, 65) Similarly, another study showed that these “memorylike NK cells” are defective in the Syk-dependent stimulati”