MEF2C regulates NK cell effector functions through control of lipid metabolism.

Natural killer (NK) cells are a critical first line of defense against viral infection. Rare mutations in a small subset of transcription factors can result in decreased NK cell numbers and function in humans, with an associated increased susceptibility to viral infection. However, our understanding of the specific transcription factors governing mature human NK cell function is limited. Here we use a non-viral CRISPR-Cas9 knockout screen targeting genes encoding 31 transcription factors differentially expressed during human NK cell development. We identify myocyte enhancer factor 2C (MEF2C) as a master regulator of human NK cell functionality ex vivo. MEF2C-haploinsufficient patients and mice displayed defects in NK cell development and effector function, with an increased susceptibility to viral infection. Mechanistically, MEF2C was required for an interleukin (IL)-2- and IL-15-mediated increase in lipid content through regulation of sterol regulatory element-binding protein (SREBP) pathways. Supplementation with oleic acid restored MEF2C-deficient and MEF2C-haploinsufficient patient NK cell cytotoxic function. Therefore, MEF2C is a critical orchestrator of NK cell antiviral immunity by regulating SREBP-mediated lipid metabolism.

Sterile liver injury induces a protective tissue-resident cDC1-ILC1 circuit through cDC1-intrinsic cGAS-STING-dependent IL-12 production.

Tissue-resident immune cells are critical to the initiation and potentiation of inflammation. However, the tissue-protective cellular communication networks initiated by resident immunity during sterile inflammation are not well understood. Using single-cell transcriptomic analysis, we show the liver-resident cell connectome and signalome during acute liver injury. These analyses identify Il12b as a central regulator of liver injury-associated changes in gene expression. Interleukin (IL)-12 produced by conventional type 1 dendritic cells (cDC1s) is required for protection during acute injury through activation of interferon (IFN)-γ production by liver-resident type 1 innate lymphoid cells (ILC1s). Using a targeted in vivo CRISPR-Cas9 screen of innate immune sensing pathways, we find that cDC1-intrinsic cGAS-STING signaling acts upstream of IL-12 production to initiate early protective immune responses. Our study identifies the core communication hubs initiated by tissue-resident innate immune cells during sterile inflammation in vivo and implicates cDC1-derived IL-12 as an important regulator of this process.

Adipose cDC1s contribute to obesity-associated inflammation through STING-dependent IL-12 production.

Obesity is associated with chronic low-grade white adipose tissue (WAT) inflammation that can contribute to the development of insulin resistance in mammals. Previous studies have identified interleukin (IL)-12 as a critical upstream regulator of WAT inflammation and metabolic dysfunction during obesity. However, the cell types and mechanisms that initiate WAT IL-12 production remain unclear. Here we show that conventional type 1 dendritic cells (cDC1s) are the cellular source of WAT IL-12 during obesity through analysis of mouse and human WAT single-cell transcriptomic datasets, IL-12 reporter mice and IL-12p70 protein levels by enzyme-linked immunosorbent assay. We demonstrate that cDC1s contribute to obesity-associated inflammation by increasing group 1 innate lymphocyte interferon-γ production and inflammatory macrophage accumulation. Inducible depletion of cDC1s increased WAT insulin sensitivity and systemic glucose tolerance during diet-induced obesity. Mechanistically, endocytosis of apoptotic bodies containing self-DNA by WAT cDC1s drives stimulator of interferon genes (STING)-dependent IL-12 production. Together, these results suggest that WAT cDC1s act as critical regulators of adipose tissue inflammation and metabolic dysfunction during obesity.