Transcriptional and chromatin profiling of human blood innate lymphoid cell subsets sheds light on HIV‐1 pathogenesis.

Innate lymphoid cells (ILCs) are a diverse population of cells that include NK cells and contribute to tissue homeostasis and repair, inflammation, and provide protection from infection. The interplay between human blood ILCs, as well as their responses to HIV‐1 infection, remains poorly understood. This study used transcriptional and chromatin profiling to explore these questions. Transcriptional profiling and flow cytometry analysis support that there are four main ILC subsets found in human blood. Unlike in mice, human NK cells expressed the tissue repair protein amphiregulin (AREG). AREG production was induced by TCF7/WNT, IL‐2, and IL‐15, and inhibited by TGFB1, a cytokine increased in people living with HIV‐1. In HIV‐1 infection, the percentage of AREG+ NK cells correlated positively with the numbers of ILCs and CD4+ T cells but negatively with the concentration of inflammatory cytokine IL‐6. NK‐cell knockout of the TGFB1‐stimulated WNT antagonist RUNX3 increased AREG production. Antiviral gene expression was increased in all ILC subsets from HIV‐1 viremic people, and anti‐inflammatory gene MYDGF was increased in an NK‐cell subset from HIV‐1‐infected people whose viral load was undetectable in the absence of antiretroviral therapy. The percentage of defective NK cells in people living with HIV‐1 correlated inversely with ILC percentage and CD4+ T‐cell counts. CD4+ T cells and their production of IL‐2 prevented the loss of NK‐cell function by activating mTOR. These studies clarify how ILC subsets are interrelated and provide insight into how HIV‐1 infection disrupts NK cells, including an uncharacterized homeostatic function in NK cells. Synopsis: The complex interplay between human blood innate lymphoid cells (ILCs) and natural killer (NK) cells, as well as their responses to HIV‐1 infection, remains poorly understood. In this study, we provide a more comprehensive understanding of the relationship among these cellular subsets, uncover a novel homeostatic function in human NK cells, and illuminate how HIV‐1 infection disrupts these cellular subsets and their functions.Human blood CD56hi NK cells inhabit an intermediary state between ILCs and a cluster comprising CD56dim and CD56− NK cells.In contrast to mice, human NK cells are major producers of the homeostatic cytokine amphiregulin (AREG).The production of AREG by NK cells is WNT/TCF7‐dependent and inhibited by TGFB1 and RUNX3. Furthermore, its production is reduced in people living with HIV‐1.During HIV‐1 infection, nonfunctional, MTOR‐deficient, CD56− NK cells are generated from epigenetically similar CD56dim NK cells, a process influenced by deficits in CD4+ T cells and IL‐2. [ABSTRACT FROM AUTHOR]