Natural killer (NK) cells function by eliminating virus-infected or tumor cells. Here we identified an NK-lineage-biased progenitor population, referred to as early NK progenitors (ENKPs), which developed into NK cells independently of common precursors for innate lymphoid cells (ILCPs). ENKP-derived NK cells (ENKP_NK cells) and ILCP-derived NK cells (ILCP_NK cells) were transcriptionally different. We devised combinations of surface markers that identified highly enriched ENKP_NK and ILCP_NK cell populations in wild-type mice. Furthermore, Ly49H+ NK cells that responded to mouse cytomegalovirus infection primarily developed from ENKPs, whereas ILCP_NK cells were better IFNγ producers after infection with Salmonella and herpes simplex virus. Human CD56dim and CD56bright NK cells were transcriptionally similar to ENKP_NK cells and ILCP_NK cells, respectively. Our findings establish the existence of two pathways of NK cell development that generate functionally distinct NK cell subsets in mice and further suggest these pathways may be conserved in humans.
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The polymorphism of the gene FAM13A (family with sequence similarity 13, member A) is strongly linked to the risk of lung cancer and chronic obstructive pulmonary disease, which are among the leading causes of mortality and morbidity in lung-related diseases worldwide. However, the underlying molecular and cellular mechanisms through which FAM13A contributes to the pathogenesis of these diseases largely remain unclear. Here, using a Fam13a knock out (KO) mouse model, we showed that Fam13a depletion upregulated the expression of the terminal differentiation and inhibitory marker, KLRG1 (killer cell lectin-like receptor G1) in natural killer (NK) cells. NK cells from Fam13a -deficient mice showed impaired IFN-γ production either against target tumor cells or following various cytokine cocktail stimulations. Furthermore, the number of lung metastases induced by B16F10 melanoma cells was increased in Fam13a -KO mice. Collectively, our data suggest a key role of FAM13A in regulating NK cell functions, indicating that the key lung-disease risk gene FAM13A might contribute to the pathogenesis of several lung diseases via regulating NK cells.

Interferon-gamma (IFNG) augments immune function yet promotes T cell exhaustion through PDL1. How these opposing effects are integrated to impact immune checkpoint blockade (ICB) is unclear. We show that while inhibiting tumor IFNG signaling decreases interferon-stimulated genes (ISGs) in cancer cells, it increases ISGs in immune cells by enhancing IFNG produced by exhausted T cells (TEX). In tumors with favorable antigenicity, these TEX mediate rejection. In tumors with neoantigen or MHC-I loss, TEX instead utilize IFNG to drive maturation of innate immune cells, including a PD1+TRAIL+ ILC1 population. By disabling an inhibitory circuit impacting PD1 and TRAIL, blocking tumor IFNG signaling promotes innate immune killing. Thus, interferon signaling in cancer cells and immune cells oppose each other to establish a regulatory relationship that limits both adaptive and innate immune killing. In melanoma and lung cancer patients, perturbation of this relationship is associated with ICB response independent of tumor mutational burden.
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