Clarification of human blood ILC subtype interrelatedness and discovery of amphiregulin production by human NK cells shed light on HIV-1 pathogenesis

The interrelatedness of human blood innate lymphoid cell (ILC) subsets, and how they are perturbed by HIV-1, remains unclear. Transcriptional and chromatin profiling separated blood ILCs into ILC2s, ILCPs, one cluster that included CD56dim and CD56-NK cells, and CD56hiNK cells that have features of both CD56dim/-NK cells and ILCs. In contrast to mice, human NK cells expressed tissue repair protein amphiregulin (AREG), with greater production by CD56hiNK cells than by ILCs. AREG was induced by TCF7/WNT signaling, IL-2, or IL-15, but not by inflammatory cytokines, and was inhibited by TGFB1, a cytokine elevated in people living with HIV-1. NK cell knockout of the TGFB1-stimulated WNT antagonist RUNX3 increased AREG production. In people living with HIV-1, AREG+NK cell percentage correlated with numbers of ILCs and CD4+T cells, and correlated inversely with inflammatory cytokine IL-6. RNA-Seq showed increased antiviral gene expression in all ILC subsets from people who were HIV-1 viremic, and increased expression of anti-inflammatory gene MYDGF in CD56hiNK cells from elite controllers. Functionally-defective CD56-NK cells were increased in people living with HIV-1 in inverse correlation with CD56dimNK cells, ILCs, and CD4+T cells. Experiments with human PBMCs ex vivo and in humanized mice revealed that CD4+T cells and their production of IL-2 prevented CD56dim transition to CD56-NK cells by activating mTOR, and, in people living with HIV-1, plasma IL-2 correlated with CD4+T cell number but not with CD8+T cells. These studies clarify how ILC subsets are interrelated and provide insight into how HIV-1 infection disrupts NK cells, including homeostatic functions of NK cells discovered here. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/440368v3_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@9d6be2org.highwire.dtl.DTLVardef@115f0e8org.highwire.dtl.DTLVardef@17b1a28org.highwire.dtl.DTLVardef@f262e9_HPS_FORMAT_FIGEXP M_FIG C_FIG