Liver type 1 innate lymphoid cells lacking IL-7 receptor are a native killer cell subset fostered by parenchymal niches
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eLife assessment
This study provides important insights on the developmental process and functional heterogeneity of liver ILC1s, especially how IL-7R+ and IL-7R- ILC1s are generated. Authors present compelling evidence on the dependence of ILC1s on IL-7R- precursor and their reliance on IL-15 to develop cytotoxic functions. The work will be of broad interest to immunologists and liver biologists.
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Abstract
Group 1 innate lymphoid cells (G1-ILCs), including circulating natural killer (NK) cells and tissue-resident type 1 ILCs (ILC1s), are innate immune sentinels critical for responses against infection and cancer. In contrast to relatively uniform NK cells through the body, diverse ILC1 subsets have been characterized across and within tissues in mice, but their developmental and functional heterogeneity remain unsolved. Here, using multimodal in vivo approaches including fate-mapping and targeting of the interleukin 15 (IL-15)-producing microenvironment, we demonstrate that liver parenchymal niches support the development of a cytotoxic ILC1 subset lacking IL-7 receptor (7 R − ILC1s). During ontogeny, fetal liver (FL) G1-ILCs arise perivascularly and then differentiate into 7 R − ILC1s within sinusoids. Hepatocyte-derived IL-15 supports parenchymal development of FL G1-ILCs to maintain adult pool of 7 R − ILC1s. IL-7R + (7R + ) ILC1s in the liver, candidate precursors for 7 R − ILC1s, are not essential for 7 R − ILC1 development in physiological conditions. Functionally, 7 R − ILC1s exhibit killing activity at steady state through granzyme B expression, which is underpinned by constitutive mTOR activity, unlike NK cells with exogenous stimulation-dependent cytotoxicity. Our study reveals the unique ontogeny and functions of liver-specific ILC1s, providing a detailed interpretation of ILC1 heterogeneity.
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eLife assessment
This study provides important insights on the developmental process and functional heterogeneity of liver ILC1s, especially how IL-7R+ and IL-7R- ILC1s are generated. Authors present compelling evidence on the dependence of ILC1s on IL-7R- precursor and their reliance on IL-15 to develop cytotoxic functions. The work will be of broad interest to immunologists and liver biologists.
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Reviewer #1 (Public Review):
This work endeavours to delineate the relationship between IL-7R+ and IL-7R- ILC1 in the liver. They elegantly utilize a PLZF reporting system to identify the progenitor/product relationship between ILC subsets and show that ILC1s emerge separately from NK cells and LTi cells.
Furthermore, ILC1 are enriched in the liver. Extending this work in Rora-deficient mice, they demonstrate that over time, these cells are poorly replaced in the liver, and that IL-7R+ cells did not convert into IL-7R- cells at steady-state. Fetal liver IL-7R+ ILC1s were shown to partially contribute to mature ILC1s. Interestingly, they show that there were localization changes between ILC1 precursors and mature ILC1s in the liver. They then analysed the factors that might underpin these different localizations by examining IL-15 which …
Reviewer #1 (Public Review):
This work endeavours to delineate the relationship between IL-7R+ and IL-7R- ILC1 in the liver. They elegantly utilize a PLZF reporting system to identify the progenitor/product relationship between ILC subsets and show that ILC1s emerge separately from NK cells and LTi cells.
Furthermore, ILC1 are enriched in the liver. Extending this work in Rora-deficient mice, they demonstrate that over time, these cells are poorly replaced in the liver, and that IL-7R+ cells did not convert into IL-7R- cells at steady-state. Fetal liver IL-7R+ ILC1s were shown to partially contribute to mature ILC1s. Interestingly, they show that there were localization changes between ILC1 precursors and mature ILC1s in the liver. They then analysed the factors that might underpin these different localizations by examining IL-15 which is highly produced by macrophages and endothelial cells. They identify that hepatocyte-derived IL-15 supports the development of 7R− ILC1s in the parenchyma to maintain adult 7R− ILC1s within the sinusoids. Finally, the authors addressed the discrepancy in understanding of cytotoxicity expressed by ILC1s and identify that constitutive expression of mTOR was necessary to effect this function, thereby providing a mechanistic explanation for variable cytotoxicity observed in other studies. Overall, this study advances our knowledge of how ILC1 are generated and maintained in the liver, and how they acquire their effector functions.
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Reviewer #2 (Public Review):
The authors are aiming to characterize the developmental process and functional heterogeneity of liver ILC1s. The role of liver ILC1's in human health is still unknown. ILC1's are abundant in fetal liver and decline throughout development into adults.
The authors have gone to great lengths to establish the relationship between IL-7R expression and ILC1 ontogeny.
The study provides insight into the complex ILC1 ontogeny by revealing relationships among heterogenous ILC1 subsets.
The data suggests intrinsic cytotoxic programs of 7R− ILC1s differ to NK cells, proposing them as critical steady-state sentinels against infection prevention and tumor surveillance.
The big unresolved question is why ILC1 dominate fetal innate lymphocytes versus NK cells in adult life.
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