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 hypermethylation. Genome-wide DNA methylation patterns were strikingly similar between HCMV-associated adaptive NK cells and cytotoxic effector Tcells 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 Tcells. 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.
Bibliographical noteFunding Information:
This work was supported by the European Research Council under the European Union’s Seventh Framework Programme (FP/2007-2013)/ERC Grant Agreement no. 311335, Swedish Research Council, Swedish Foundation for Strategic Research, Swedish Cancer Foundation, Swedish Children’s Cancer Foundation, Knut and Alice Wallenberg Foundation, the Karolinska Institute Research Foundation, the Frontiers in Biomedical Research Fellowship, and University of Minnesota T32 Haematology Training Grant. We thank Marcus Holm, Uppsala Multidisciplinary Center for Advanced Computational Science, for writing data pre- and post-processing code enabling usage of Barnes-Hut t-SNE, the Karolinska Institutet Bioinformatics and Expression Analysis core facility, supported by the Karolinska Institiutet Board of Research and the Karolinska Hospital Research Committee, for assistance with arrays, and Iyadh Douagi for assistance with cell sorting.