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Summary: Group 1 innate lymphoid cells (ILCs), comprising ILC1s and natural killer cells (NK cells), belong to a large family of developmentally related innate lymphoid cells that lack rearranged antigen‐specific receptors. NK cells and ILC1s both require the transcription factor T‐bet for lineage commitment but additionally rely on Eomes and Hobit, respectively, for their development and effector maturation programs. Both ILC1s and NK cells are essential for rapid responses against infections and mediate cancer immunity through production of effector cytokines and cytotoxicity mediators. ILC1s are enriched in tissues and hence generally considered tissue resident cells whereas NK cells are often considered circulatory. Despite being deemed different cell types, ILC1s and NK cells share many common features both phenotypically and functionally. Recent studies employing single cell RNA sequencing (scRNA‐seq) technology have exposed previously unappreciated heterogeneity in group 1 ILCs and further broaden our understanding of these cells. Findings from these studies imply that ILC1s in different tissues and organs share a common signature but exhibit some unique characteristics, possibly stemming from tissue imprinting. Also, data from recent fate mapping studies employing Hobit, RORγt, and polychromic reporter mice have greatly advanced our understanding of the developmental and effector maturation programs of these cells. In this review, we aim to outline the fundamental traits of mouse group 1 ILCs and explore recent discoveries related to their developmental programs, phenotypic heterogeneity, plasticity, and transcriptional regulation. [ABSTRACT FROM AUTHOR]

ABSTRACTHypercaloric diets overactivate the intestinal immune system and disrupt the microbiome and epithelial cell functions, impairing glucose metabolism. The origins of this inflammatory cascade are poorly characterized. We investigated the involvement of intestinal proinflammatory group 1 innate lymphoid cells (ILC1s) in obesity progression and metabolic disruption. In obese mice, we studied longitudinally the ILC1s response to the diet and ILC1s depletion to address its role in obesity. ILC1s are required for the expansion of pro-inflammatory macrophages and ILC2s. ILC1s depletion induced the ILC3-IL-22 pathway, increasing mucin production, antimicrobial peptides, and neuroendocrine cells. These changes were translated into higher gut hormones and reduced insulinemia and adiposity. ILC1s depletion was also associated with a bloom in Akkermansia muciniphila and decreases in Bilophila spp. Intestinal-ILC1s are upstream activators of inflammatory signals, connecting immunity with the microbiome, the enteroendocrine system, and the intestinal barrier in the control of glucose metabolism and adiposity.

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.

Type 1 Innate Lymphoid cells (ILC1s) are tissue‐resident cells that partake in the regulation of inflammation and homeostasis. A major feature of ILC1s is their ability to rapidly respond after infections. The effector repertoire of ILC1s includes the pro‐inflammatory cytokines IFN‐γ and TNF‐α and cytotoxic mediators such as granzymes, which enable ILC1s to establish immune responses and to directly kill target cells. Recent advances in the characterization of ILC1s have considerably furthered our understanding of ILC1 development and maintenance in tissues. In particular, it has become clear how ILC1s operate independently from conventional natural killer cells, with which they share many characteristics. In this review, we discuss recent developments with regards to the differentiation, polarization, and effector maturation of ILC1s. These processes may underlie the observed heterogeneity in ILC1 populations within and between different tissues. Next, we highlight transcriptional programs that control each of the separate steps in the differentiation of ILC1s. These transcriptional programs are shared with other tissue‐resident type‐1 lymphocytes, such as tissue‐resident memory T cells (TRM) and invariant natural killer T cells (iNKT), highlighting that ILC1s utilize networks of transcriptional regulation that are conserved between lymphocyte lineages to respond effectively to tissue‐invading pathogens. [ABSTRACT FROM AUTHOR]

The development of innate lymphoid cell (ILC) transcription factor reporter mice has shown a previously unexpected complexity in ILC hematopoiesis. Using novel polychromic mice to achieve higher phenotypic resolution, we have characterized bone marrow progenitors that are committed to the group 1 ILC lineage. These common ILC1/NK cell progenitors (ILC1/NKP), which we call "aceNKPs", are defined as lineage-Id2+IL- 7Ra+CD25-a4ß7-NKG2A/C/E+Bcl11b-. In vitro, aceNKPs differentiate into group 1 ILCs, including NK-like cells that express Eomes without the requirement for IL-15, and produce IFN-γ and perforin upon IL-15 stimulation. Following reconstitution of Rag2-/-Il2rg-/- hosts, aceNKPs give rise to a spectrum of mature ILC1/NK cells (regardless of their tissue location) that cannot be clearly segregated into the traditional ILC1 and NK subsets, suggesting that group 1 ILCs constitute a dynamic continuum of ILCs that can develop from a common progenitor. In addition, aceNKP-derived ILC1/NK cells effectively ameliorate tumor burden in a model of lung metastasis, where they acquired a cytotoxic NK cell phenotype. Our results identify the primary ILC1/NK progenitor that lacks ILC2 or ILC3 potential and is strictly committed to ILC1/NK cell production irrespective of tissue homing. [ABSTRACT FROM AUTHOR]

Abstract Purpose Human innate lymphoid cells (hILCs) are lineage‐negative immune cells that do not express rearranged adaptive antigen receptors. Natural killer (NK) cells are hILCs that contribute to cancer defense. The role of non‐NK hILCs in cancer is unclear. Our study aimed to characterize non‐NK hILCs in bladder cancer. Experimental design Mass cytometry was used to characterize intratumoral non‐NK hILCs based on 35 parameters, including receptors, cytokines, and transcription factors from 21 muscle‐invasive bladder tumors. Model‐based clustering was performed on t‐distributed stochastic neighbor embedding (t‐SNE) coordinates of hILCs, and the association of hILCs with tumor stage was analyzed. Results Most frequent among intratumoral non‐NK hILCs were hILC1s, which were increased in higher compared with lower stage tumors. Intratumoral hILC1s were marked by Th17‐like phenotype with high RORγt, IL‐17, and IL‐22 compared to Th1 differentiation markers, including Tbet, perforin, and IFN‐γ. Compared with intratumoral hILC2s and hILC3s, hILC1s also had lower expression of activation markers (NKp30, NKp46, and CD69) and increased expression of exhaustion molecules (PD‐1 and Tim3). Unsupervised clustering identified nine clusters of bladder hILCs, which were not defined by the primary hILC subtypes 1–3. hILC1s featured in all the nine clusters indicating that intratumoral hILC1s displayed the highest phenotypic heterogeneity among all hILCs. Conclusions hILC1s are increased in higher stage tumors among patients with muscle‐invasive bladder cancer. These intratumoral hILC1s exhibit an exhausted phenotype and Th17‐like differentiation, identifying them as potential targets for immunotherapy.

Purpose: Human innate lymphoid cells (hILCs) are lineage‐negative immune cells that do not express rearranged adaptive antigen receptors. Natural killer (NK) cells are hILCs that contribute to cancer defense. The role of non‐NK hILCs in cancer is unclear. Our study aimed to characterize non‐NK hILCs in bladder cancer. Experimental design: Mass cytometry was used to characterize intratumoral non‐NK hILCs based on 35 parameters, including receptors, cytokines, and transcription factors from 21 muscle‐invasive bladder tumors. Model‐based clustering was performed on t‐distributed stochastic neighbor embedding (t‐SNE) coordinates of hILCs, and the association of hILCs with tumor stage was analyzed. Results: Most frequent among intratumoral non‐NK hILCs were hILC1s, which were increased in higher compared with lower stage tumors. Intratumoral hILC1s were marked by Th17‐like phenotype with high RORγt, IL‐17, and IL‐22 compared to Th1 differentiation markers, including Tbet, perforin, and IFN‐γ. Compared with intratumoral hILC2s and hILC3s, hILC1s also had lower expression of activation markers (NKp30, NKp46, and CD69) and increased expression of exhaustion molecules (PD‐1 and Tim3). Unsupervised clustering identified nine clusters of bladder hILCs, which were not defined by the primary hILC subtypes 1–3. hILC1s featured in all the nine clusters indicating that intratumoral hILC1s displayed the highest phenotypic heterogeneity among all hILCs. Conclusions: hILC1s are increased in higher stage tumors among patients with muscle‐invasive bladder cancer. These intratumoral hILC1s exhibit an exhausted phenotype and Th17‐like differentiation, identifying them as potential targets for immunotherapy. [ABSTRACT FROM AUTHOR]

Innate lymphoid cells (ILCs) are tissue resident cells with organ-specific properties. Here, we show that the central nervous system (CNS) encompasses ILCs. In particular, CD3−NK1.1+ cells present in the murine CNS comprise natural killer (NK) cells, ILC1s, intermediate ILC1s (intILC1s) and ex-ILC3s. We investigated the properties of CNS-ILC1s in comparison with CNS-NK cells during steady state and experimental autoimmune encephalomyelitis (EAE). ILC1s characteristically express CXCR3, CXCR6, DNAM-1, TRAIL, and CD200R and display heightened TNF-α production upon stimulation. In addition, ILC1s express perforin and are able to degranulate, although in a lesser extent than NK cells. Within the CNS compartments, ILC1s are enriched in the choroid plexus where very few NK cells are present, and also reside in the brain parenchyma and meninges. During EAE, ILC1s maintain stable IFN-γ and TNF-α levels while in NK cells the production of these cytokines increases as EAE progresses. Moreover, the amount of ILC1s and intILC1s increase in the parenchyma during EAE, but in contrast to NK cells, they show no signs of local proliferation. The upregulation in the inflamed brain of chemokines involved in ILC1 migration, such as CXCL9, CXCL10, and CXCL16 may lead to a recruitment of ILC1s from meninges or choroid plexus into the brain parenchyma. In sum, CNS-ILC1 phenotype, distribution and moderate inflammatory response during EAE suggest that they may act as gatekeepers involved in the control of neuroinflammation.

Innate lymphoid cells (ILCs) are tissue resident cells with organ-specific properties. Here, we show that the central nervous system (CNS) encompasses ILCs. In particular, CD3−NK1.1+ cells present in the murine CNS comprise natural killer (NK) cells, ILC1s, intermediate ILC1s (intILC1s) and ex-ILC3s. We investigated the properties of CNS-ILC1s in comparison with CNS-NK cells during steady state and experimental autoimmune encephalomyelitis (EAE). ILC1s characteristically express CXCR3, CXCR6, DNAM-1, TRAIL, and CD200R and display heightened TNF-α production upon stimulation. In addition, ILC1s express perforin and are able to degranulate, although in a lesser extent than NK cells. Within the CNS compartments, ILC1s are enriched in the choroid plexus where very few NK cells are present, and also reside in the brain parenchyma and meninges. During EAE, ILC1s maintain stable IFN-γ and TNF-α levels while in NK cells the production of these cytokines increases as EAE progresses. Moreover, the amount of ILC1s and intILC1s increase in the parenchyma during EAE, but in contrast to NK cells, they show no signs of local proliferation. The upregulation in the inflamed brain of chemokines involved in ILC1 migration, such as CXCL9, CXCL10, and CXCL16 may lead to a recruitment of ILC1s from meninges or choroid plexus into the brain parenchyma. In sum, CNS-ILC1 phenotype, distribution and moderate inflammatory response during EAE suggest that they may act as gatekeepers involved in the control of neuroinflammation. [ABSTRACT FROM AUTHOR]

Summary Natural killer (NK) cells and non-cytotoxic interferon-γ (IFN-γ)-producing group I innate lymphoid cells (ILC1s) produce large amounts of IFN-γ and cause activation of innate and adaptive immunity. However, how NKs and ILC1s are primed during infection remains elusive. Here we have shown that a lymphocyte subpopulation natural killer-like B (NKB) cells existed in spleen and mesenteric lymph nodes (MLNs). NKBs had unique features that differed from T and B cells, and produced interleukin-18 (IL-18) and IL-12 at an early phase of infection. NKB cells played a critical role in eradication of microbial infection via secretion of IL-18 and IL-12. Moreover, IL-18 deficiency abrogated the antibacterial effect of NKBs. Upon bacterial challenge, NKB precursors (NKBPs) rapidly differentiated to NKBs that activated NKs and ILC1s against microbial infection. Our findings suggest that NKBs might be exploited to develop effective therapies for treatment of infectious diseases. [ABSTRACT FROM AUTHOR]

• ILCs play complex and diverse roles in macrophages development, homeostasis, polarization, inflammation, or viral infection. • ILCs regulate a wider range of immune responses through functional interactions with macrophages. They work together to coordinate the immune response of the organs of the whole body to control tissue homeostasis or cause immune disorders. Innate lymphoid cells (ILCs) and macrophages are tissue-resident cells that play important roles in tissue-immune homeostasis and immune regulation. ILCs are mainly distributed on the barrier surfaces of mammals to ensure immunity or tissue homeostasis following host, microbial, or environmental stimulation. Their complex relationships with different organs enable them to respond quickly to disturbances in environmental conditions and organ homeostasis, such as during infections and tissue damage. Gradually emerging evidence suggests that ILCs also play complex and diverse roles in macrophage development, homeostasis, polarization, inflammation, and viral infection. In turn, macrophages also determine the fate of ILCs to some extent, which indicates that network crossover between these interactions is a key determinant of the immune response. More work is needed to better define the crosstalk of ILCs with macrophages in different tissues and demonstrate how it is affected during inflammation and other diseases. Here, we summarize current research on the functional interactions between ILCs and macrophages and consider the potential therapeutic utility of these interactions for the benefit of human health. [ABSTRACT FROM AUTHOR]

Innate lymphoid cells (ILCs) are tissue-resident lymphocytes differing from conventional T lymphocytes in having no antigen-specific receptors. ILCs include natural killer (NK) cells, helper-like ILC1s, ILC2s, and ILC3s, and lymphoid tissue-inducer (LTi) cells. Tumor ILCs are frequently found in various cancers, but their roles in cancer immunity and immunotherapy remain largely unclear. We report here the single-cell characterization of blood and gut helper-like ILC subsets in healthy conditions and in colorectal cancer (CRC). The healthy gut contains ILC1s, ILC3s, and ILC3/NKs, but no ILC2s. Additional tumor-specific ILC1-like and ILC2 subsets were identified in CRC patients. Signaling lymphocytic activation molecule family member 1 (SLAMF1) was found to be selectively expressed on tumor-specific ILCs, and higher levels of SLAMF1 + ILCs were observed in the blood of CRC patients. The SLAMF1-high group of CRC patients had a significantly higher survival rate than the SLAMF1-low group, suggesting that SLAMF1 is an anti-tumor biomarker in CRC., Competing Interests: E.V. is an Innate Pharma employee. Patents related to this work were under application., (© 2021 The Authors.)