Michael A Brehm

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.

Agents that induce inflammation have been used since the 18th century for the treatment of cancer. The inflammation induced by agents such as Toll-like receptor agonists is thought to stimulate tumor-specific immunity in patients and augment control of tumor burden. While NOD-scid IL2rγnull mice lack murine adaptive immunity (T cells and B cells), these mice maintain a residual murine innate immune system that responds to Toll-like receptor agonists. Here we describe a novel NOD-scid IL2rγnull mouse lacking murine TLR4 that fails to respond to lipopolysaccharide. NSG-Tlr4null mice support human immune system engraftment and enable the study of human-specific responses to TLR4 agonists in the absence of the confounding effects of a murine response. Our data demonstrate that specific stimulation of TLR4 activates human innate immune systems and delays the growth kinetics of a human patient-derived xenograft melanoma tumor.