Embryonic and neonatal waves generate distinct populations of hepatic ILC1s

Abstract

Group 1 innate lymphoid cells (ILCs) comprising circulating natural killer (cNK) cells and tissue-resident ILC1s are critical for host defense against pathogens and tumors. Despite a growing understanding of their role in homeostasis and disease, the ontogeny of group 1 ILCs remains largely unknown. Here, we used fate mapping and single-cell transcriptomics to comprehensively investigate the origin and turnover of murine group 1 ILCs. Whereas cNK cells are continuously replaced throughout life, we uncovered tissue-dependent development and turnover of ILC1s. A first wave of ILC1s emerges during embryogenesis in the liver and transiently colonizes fetal tissues. After birth, a second wave quickly replaces ILC1s in most tissues apart from the liver, where they layer with embryonic ILC1s, persist until adulthood, and undergo a specific developmental program. Whereas embryonically derived ILC1s give rise to a cytotoxic subset, the neonatal wave establishes the full spectrum of ILC1s. Our findings uncover key ontogenic features of murine group 1 ILCs and their association with cellular identities and functions.

Liver type 1 innate lymphoid cells lacking IL-7 receptor are a native killer cell subset fostered by parenchymal niches

“…After tamoxifen injection into pregnant mice at E17.5, liver of neonatal and 4 weeks old pups were analyzed. TdTomato expression was clearly restricted to IL-7R − fractions within neonatal G1-ILCs and AL ILC1s (Figure 3C–3E, Figure 3–figure supplement 1A), consistent with previous studies (Chen et al, 2022; Sparano et al, 2022). As shown in these studies, fate-mapped 7R − ILC1s showed a skewed expression of Ly49E/F, though they also contained Ly49E/F − population (20–25%) (Figure 3–figure supplement 1B–1D).…”

“…FL G1-ILCs highly expressed CXCR6, TRAIL, and CD200R, resembling adult tissue ILC1s, though they completely lacked IL-7R expression (Figure 1B and 1C). AL contains both IL-7R-negative (7R − ) and -positive (7R + ) ILC1s (Figure 1C), as reported previously (Friedrich et al, 2021; Sparano et al, 2022; Yomogida et al, 2021). In contrast, CD49a + CD49b lo ILC1s in bone marrow (BM), corresponding to previously reported immature ILC1s (iILC1s) that have ability to give rise to liver ILC1s (Klose et al, 2014), were mostly IL-7R + , similar to other tissues including the spleen, mesenteric lymph nodes, peritoneal cavity, and small intestines (Figure 1C and 1D).…”

“…ILC1 heterogeneity has been extensively addressed recently. In the liver, ILC1s are separated into IL-7R − and IL-7R + populations (Friedrich et al, 2021; Sparano et al, 2022; Yomogida et al, 2021), the latter of which can differentiate into the former when cultured in vitro or transferred into lymphopenic mice (Friedrich et al, 2021). However, we show that 7R − and 7R + ILC1s behave like independent subsets under physiological conditions: decline of 7R − ILC1s and accumulation of 7R + ILC1s with age, requirements for RORα specifically in 7R + ILC1s, and phenotypical stability between 7R − and 7R + ILC1s when transferred into WT host mice.…”

“…Recent high-resolution analysis has uncovered ILC1 heterogeneity and development. Liver ILC1s are separated into IL-7R-negative (7R − ) and -positive (7R + ) subsets (Friedrich et al, 2021; Sparano et al, 2022; Yomogida et al, 2021). G1-ILCs in the fetal liver (FL) are identified as precursors of ILC1s (Chen et al, 2022; Sparano et al, 2022), especially of Ly-49E + ILC1s that are included in 7R − ILC1s (Chen et al, 2022).…”

“…Liver ILC1s are separated into IL-7R-negative (7R − ) and -positive (7R + ) subsets (Friedrich et al, 2021; Sparano et al, 2022; Yomogida et al, 2021). G1-ILCs in the fetal liver (FL) are identified as precursors of ILC1s (Chen et al, 2022; Sparano et al, 2022), especially of Ly-49E + ILC1s that are included in 7R − ILC1s (Chen et al, 2022). In addition, 7R + ILC1s in the liver, salivary glands (SG), and small intestines can give rise to 7R − ILC1s in response to cytokines and inflammations (Friedrich et al, 2021), suggesting that 7R + ILC1s are also potential precursors for 7R − ILC1s.…”