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Decidual and uterine natural killer (NK) cells have been shown to contribute to the successful pregnancy both in humans and mice. NK cells represent \"cytotoxic\" group 1 innate lymphoid cells (ILCs) and are distinct from the recently described \"helper\" ILC1. Here, we show that both in humans and mice the majority of group 1 ILC in endometrium/uterus and decidua express Eomesodermin (Eomes), thus suggesting that they are developmentally related to conventional NK cells. However, they differ from peripheral NK cells. In humans, Eomes(+) decidual NK (dNK) cells express CD49a and other markers of tissue residency, including CD103, integrin β7, CD9, and CD69. The expression of CD103 allows the identification of different subsets of IFNγ-producing Eomes(+) NK cells. We show that TGFβ can sustain/induce CD103 and CD9 expression in dNK cells and decidual CD34-derived NK cells, indicating that the decidual microenvironment can instruct the phenotype of Eomes(+) NK cells. In murine decidua and uterus, Eomes(+) cells include CD49a(-)CD49b(+) conventional NK cells and CD49a(+) cells. Notably, Eomes(+)CD49a(+) cells are absent in spleen and liver. Decidual and uterine Eomes(+)CD49a(+) cells can be dissected in two peculiar cell subsets according to CD49b expression. CD49a(+)CD49b ((-)) and CD49a(+)CD49b(+) cells are enriched in immature CD11b(low)CD27(high) cells, while CD49a(-)CD49b(+) cells contain higher percentages of mature CD11b(high)CD27(low) cells, both in uterus and decidua. Moreover, Eomes(+)CD49a(+)CD49b(-) cells decrease during gestation, thus suggesting that this peculiar subset may be required in early pregnancy rather than on later phases. Conversely, a minor Eomes(-)CD49a(+) ILC1 population present in decidua and uterus increases during pregnancy. CD49b(-)Eomes(±) cells produce mainly TNF, while CD49a(-)CD49b(+) conventional NK cells and CD49a(+)CD49b(+) cells produce both IFNγ and TNF. Thus, human and murine decidua contains unique subsets of group 1 ILCs, including Eomes(+) and Eomes(-) cells, with peculiar phenotypic and functional features. Our study contributes to re-examination of the complexity of uterine and decidual ILC subsets in humans and mice and highlights the role of the decidual microenvironment in shaping the features of these cells.

Natural Killer (NK) cells are cytotoxic lymphocytes of the innate immune system and play a critical role in anti-viral and anti-tumor responses. NK cells develop in the bone marrow from hematopoietic stem cells (HSCs) that differentiate through common lymphoid progenitors (CLPs) to NK lineage-restricted progenitors (NKPs). The orchestrated action of multiple cytokines is crucial for NK cell development and maturation. Many of these cytokines such as IL-2, IL-7, IL-12, IL-15, IL-21, IL-27, and interferons (IFNs) signal via the Janus Kinase / Signal Transducer and Activator of Transcription (JAK/STAT) pathway. We here review the current knowledge about these cytokines and the downstream signaling involved in the development and maturation of conventional NK cells and their close relatives, innate lymphoid cells type 1 (ILC1). We further discuss the role of suppressor of cytokine signaling (SOCS) proteins in NK cells and highlight their potential for therapeutic application.

The liver contains both NK cells and their less cytotoxic relatives, ILC1. Here, we investigate the role of NK cells and ILC1 in the obesity-associated condition, non-alcoholic fatty liver disease (NAFLD). In the livers of mice suffering from NAFLD, NK cells are less able to degranulate, express lower levels of perforin and are less able to kill cancerous target cells than those from healthy animals. This is associated with a decreased ability to kill cancer cells . On the other hand, we find that perforin-deficient mice suffer from less severe NAFLD, suggesting that this reduction in NK cell cytotoxicity may be protective in the obese liver, albeit at the cost of increased susceptibility to cancer. The decrease in cytotoxicity is associated with a shift toward a transcriptional profile characteristic of ILC1, increased expression of the ILC1-associated proteins CD200R1 and CD49a, and an altered metabolic profile mimicking that of ILC1. We show that the conversion of NK cells to this less cytotoxic phenotype is at least partially mediated by TGFβ, which is expressed at high levels in the obese liver. Finally, we show that reduced cytotoxicity is also a feature of NK cells in the livers of human NAFLD patients.

IntroductionThe three groups of helper innate lymphoid cells (ILCs), namely ILC1, ILC2 and ILC3, have been identified by flow cytometry by combinations of cell surface markers. Here, we review various ways ILCs are currently identified, focusing on potential problems and their solutions. The first step to identify all ILCs is to exclude other lymphocytes and myeloid cells by their lineage-specific markers (Lin). However, the Lin cocktail varies in various studies, and the definition of Lin- population containing ILCs is often ambiguous, resulting in contamination of Lin+ cells, particularly T cells.MethodWe have designed combinations of cell surface markers to identify ILC populations in various tissues of B6 mice by flow cytometry. To minimize T cell contamination, TCR/CD3ϵ antibodies were used separately from the Lin cocktail. ILCs identified by surface markers are confirmed by the expression of the transcription factors GATA3, RORγt, T-bet and Eomes.ResultILC1s in the B6 mouse liver are identified by Lin-NKp46+NK1.1+TCR/CD3ϵ−CD49a+CD49b−. However, defining ILC1s in other tissues remains a challenge. ILC2s in the lung are identified by Lin−TCR/CD3ϵ− Thy1+CD127+ST2+ whereas ILC2s in the small intestine and liver are identified by Lin−TCR/CD3ϵ−Thy1+GATA3+RORγt−. ILC3s in B6 mouse spleen, liver, lung and small intestine are identified by Lin−TCR/CD3ϵ− Thy1+CD127+RORγt+.DiscussionThe ILC population is heterogeneous and the strategies to identify ILCs have to be designed for each ILC population and tissue. Excluding T cells in all cases is crucial, and a combination of transcription factors GATA3, RORγt, T-bet, and Eomes should be used to identify ILCs. Using CD3ϵ/TCRs in a different fluorochrome not in Lin cocktail minimizes contamination of T cells specifically identify individual ILC populations in various tissues.

Since their discovery, innate lymphoid cells (ILCs) have been described as the innate counterpart of the T cells. Indeed, ILCs and T cells share many features including their common progenitors, transcriptional regulation, and effector cytokine secretion. Several studies have shown complementary and redundant roles for ILCs and T cells, leaving open questions regarding why these cells would have been evolutionarily conserved. It has become apparent in the last decade that ILCs, and rare immune cells more generally, that reside in non-lymphoid tissue have non-canonical functions for immune cells that contribute to tissue homeostasis and function. Viewed through this lens, ILCs would not be just the innate counterpart of T cells, but instead act as a link between sensory cells that monitor any changes in the environment that are not necessarily pathogenic and instruct effector cells that act to maintain body homeostasis. As these non-canonical functions of immune cells are operating in absence of pathogenic signals, it opens great avenues of research for immunologists that they now need to identify the physiological cues that regulate these cells and how the process confers a finer level of control and a greater flexibility that enables the organism to adapt to changing environmental conditions. In the review, we highlight how ILCs participate in the physiologic function of the tissue in which they reside and how physiological cues, in particular neural inputs control their homeostatic activity.

Natural killer (NK) cells are crucial to various facets of human immunity and function through direct cytotoxicity or via orchestration of the broader immune response. NK cells exist across a wide range of functional and phenotypic identities. Murine and human studies have revealed that NK cells possess substantial plasticity and can alter their function and phenotype in response to external signals. NK cells also play a critical role in tumor immunity and form the basis for many emerging immunotherapeutic approaches. NK cells can directly target and lyse malignant cells with their inherent cytotoxic capabilities. In addition to direct targeting of malignant cells, certain subsets of NK cells can mediate antibody-dependent cellular cytotoxicity (ADCC) which is integral to some forms of immune checkpoint-blockade immunotherapy. Another important feature of various NK cell subsets is to co-ordinate anti-tumor immune responses by recruiting adaptive and innate leukocytes. However, given the diverse range of NK cell identities it is unsurprising that both pro-tumoral and anti-tumoral NK cell subsets have been described. Here, NK cell subsets have been shown to promote angiogenesis, drive inflammation and immune evasion in the tumor microenvironment. To date, the signals that drive tumor-infiltrating NK cells towards the acquisition of a pro- or anti-tumoral function are poorly understood. The notion of tumor microenvironment-driven NK cell plasticity has substantial implications for the development of NK-based immunotherapeutics. This review will highlight the current knowledge of NK cell plasticity pertaining to the tumor microenvironment. Additionally, this review will pose critical and relevant questions that need to be addressed by the field in coming years.

Among the variety of tissue-resident NK-like populations recently distinguished from recirculating classical NK (cNK) cells, liver innate lymphoid cells (ILC) type 1 (ILC1s) have been shown to represent a distinct lineage that originates from a novel promyelocytic leukaemia zinc finger (PLZF)-expressing ILC precursor (ILCP) strictly committed to the ILC1, ILC2, and ILC3 lineages. Here, using PLZF-reporter mice and cell transfer assays, we studied the developmental progression of ILC1s and demonstrated substantial overlap with stages previously ascribed to the cNK lineage, including pre–pro-NK, pre-NK precursor (pre-NKP), refined NKP (rNKP), and immature NK (iNK). Although they originated from different precursors, the ILC1 and cNK lineages followed a parallel progression at early stages and diverged later at the iNK stage, with a striking predominance of ILC1s over cNKs early in ontogeny. Although a limited set of ILC1 genes depended on PLZF for expression, characteristically includingIl7r,most of these genes were also differentially expressed between ILC1s and cNKs, indicating that PLZF together with other, yet to be defined, factors contribute to the divergence between these lineages.

Background The innate lymphoid cell (ILC) family consists of NK cells, ILC type 1, 2, 3 and lymphoid tissue inducer cells. They have been shown to play important roles in homeostasis and immune responses and are generally considered tissue resident. Not much is known about the presence of ILC members within the central nervous system and whether they are tissue resident in this organ too. Therefore, we studied the presence of all ILC members within the central nervous system and after ischemic brain insult. Methods We used the photothrombotic ischemic lesion method to induce ischemic lesions within the mouse brain. Using whole-mount immunofluorescence imaging, we established that the ILCs were present at the rim of the lesion. We quantified the increase of all ILC members at different time-points after the ischemic lesion induction by flow cytometry. Their migration route via chemokine CXCL12 was studied by using different genetic mouse models, in which we induced deletion of Cxcl12 within the blood–brain barrier endothelium, or its receptor, Cxcr4 , in the ILCs. The functional role of the ILCs was subsequently established using the beam-walk sensorimotor test. Results Here, we report that ILCs are not resident within the mouse brain parenchyma during steady-state conditions, but are attracted towards the ischemic stroke. Specifically, we identify NK cells, ILC1s, ILC2s and ILC3s within the lesion, the highest influx being observed for NK cells and ILC1s. We further show that CXCL12 expressed at the blood–brain barrier is essential for NK cells and NKp46 + ILC3s to migrate toward the lesion. Complementary, Cxcr4 -deficiency in NK cells prevents NK cells from entering the infarct area. Lack of NK cell migration results in a higher neurological deficit in the beam-walk sensorimotor test. Conclusions This study establishes the lack of ILCs in the mouse central nervous system at steady-state and their migration towards an ischemic brain lesion. Our data show a role for blood–brain barrier-derived CXCL12 in attracting protective NK cells to ischemic brain lesions and identifies a new CXCL12/CXCR4-mediated component of the innate immune response to stroke.

The prevalence of obesity skyrocketed over the past decades to become a significant public health problem. Obesity is recognized as a low-grade inflammatory disease and is linked with several comorbidities such as diabetes, circulatory disease, common neurodegenerative diseases, as well as chronic pain. Adipocytes are a major neuroendocrine organ that continually, and systemically, releases pro-inflammatory factors. While the exact mechanisms driving obesity-induced pain remain poorly defined, nociceptor hypersensitivity may result from the systemic state of inflammation characteristic of obesity as well as weight surplus-induced mechanical stress. Obesity and pain also share various genetic mutations, lifestyle risk factors, and metabolic pathways. For instance, fat pads are often found hyper-innervated and rich in immune cell types of multiple origins. These immunocytes release cytokines, amplifying nociceptor function, which, in turn, via locally released neuropeptides, sustain immunocytes' function. Here, we posit that along with mechanical stress stemming from extra weight, the local neuro-immune interplay occurring within the fat pads maintains the state of chronic low-grade inflammation and heightens sensory hypersensitivity. Overall, stopping such harmful neuro-immune crosstalk may constitute a novel pathway to prevent obesity-associated comorbidities, including neuronal hypersensitivity.

Innate lymphoid cells (ILCs) are a population of lymphoid cells that do not express T cell or B cell antigen-specific receptors. They are largely tissue-resident and enriched at mucosal sites to play a protective role against pathogens. ILCs mimic the functions of CD4 T helper (Th) subsets. Type 1 innate lymphoid cells (ILC1s) are defined by the expression of signature cytokine IFN-γ and the master transcription factor T-bet, involving in the type 1 immune response; ILC2s are characterized by the expression of signature cytokine IL-5/IL-13 and the master transcription factor GATA3, participating in the type 2 immune response; ILC3s are RORγt-expressing cells and are capable of producing IL-22 and IL-17 to maintain intestinal homeostasis. The discovery and investigation of ILCs over the past decades extends our knowledge beyond classical adaptive and innate immunology. In this review, we will focus on the roles of ILCs in intestinal inflammation and related disorders.