Group 2 innate lymphocytes at the interface between innate and adaptive immunity.

Group 2 innate lymphoid cells (ILC2) are innate immune cells that respond rapidly to their environment through soluble inflammatory mediators and cell-to-cell interactions. As tissue-resident sentinels, ILC2 help orchestrate localized type 2 immune responses. These ILC2-driven type 2 responses are now recognized in diverse immune processes, different anatomical locations, and homeostatic or pathological settings. ILC2-derived cytokines and cell surface signaling molecules function as key regulators of innate and adaptive immunity. Conversely, ILC2 are governed by their environment. As such, ILC2 form an important nexus of the immune system and may present an attractive target for immune modulation in disease

Context Dependent Role of Type 2 Innate Lymphoid Cells in Allergic Skin Inflammation.

The discovery of innate lymphoid cells (ILC) has profoundly influenced the understanding of innate and adaptive immune crosstalk in health and disease. ILC and T cells share developmental and functional characteristics such as the lineage-specifying transcription factors and effector cytokines, but importantly ILC do not display rearranged antigen-specific receptors. Similar to T cells ILC are subdivided into 3 different helper-like subtypes, namely ILC1-3, and a killer-like subtype comprising natural killer (NK) cells. Increasing evidence supports the physiological relevance of ILC, e.g., in wound healing and defense against parasites, as well as their pathogenic role in allergy, inflammatory bowel diseases or psoriasis. Group 2 ILC have been attributed to the pathogenesis of allergic diseases like asthma and atopic dermatitis. Other inflammatory skin diseases such as allergic contact dermatitis are profoundly shaped by inflammatory NK cells. This article reviews the role of ILC in allergic skin diseases with a major focus on ILC2. While group 2 ILC are suggested to contribute to the pathogenesis of type 2 dominated inflammation as seen in atopic dermatitis, we have shown that lack of ILC2 in type 1 dominated contact hypersensitivity results in enhanced inflammation, suggesting a regulatory role of ILC2 in this context. We provide a concept of how ILC2 may influence context dependent the mutual counterbalance between type I and type II immune responses in allergic skin diseases

Early Neutrophilia Marked by Aerobic Glycolysis Sustains Host Metabolism and Delays Cancer Cachexia.

An elevated neutrophil-lymphocyte ratio negatively predicts the outcome of patients with cancer and is associated with cachexia, the terminal wasting syndrome. Here, using murine model systems of colorectal and pancreatic cancer we show that neutrophilia in the circulation and multiple organs, accompanied by extramedullary hematopoiesis, is an early event during cancer progression. Transcriptomic and metabolic assessment reveals that neutrophils in tumor-bearing animals utilize aerobic glycolysis, similar to cancer cells. Although pharmacological inhibition of aerobic glycolysis slows down tumor growth in C26 tumor-bearing mice, it precipitates cachexia, thereby shortening the overall survival. This negative effect may be explained by our observation that acute depletion of neutrophils in pre-cachectic mice impairs systemic glucose homeostasis secondary to altered hepatic lipid processing. Thus, changes in neutrophil number, distribution, and metabolism play an adaptive role in host metabolic homeostasis during cancer progression. Our findings provide insight into early events during cancer progression to cachexia, with implications for therapy

Lack of Type 2 Innate Lymphoid Cells Promotes a Type I-Driven Enhanced Immune Response in Contact Hypersensitivity.

Allergic contact dermatitis and its animal model, contact hypersensitivity, are T-cell-mediated inflammatory skin diseases that require activation of the innate immune system. Here we investigate the role of innate lymphoid cells (ILCs) during the elicitation phase of 2,4,6-trinitrochlorobenzene-induced contact hypersensitivity using EomesGfp/+ x Rorc(γt)-CreTg x Rosa26RYfp/+ reporter mice. Ear swelling responses, cutaneous ILC numbers, and cytokine production were determined at different time points. Functional analyses were performed in a CD90.1/.2 congenic adoptive transfer model that allowed selective antibody-mediated depletion of ILCs before hapten challenge, and in Rorasg/floxIl7rCre/+ mice, which lack ILC2. Hapten challenge induced early increases of natural killer cells in skin and ear draining lymph nodes corresponding to the peak ear swelling response. In contrast, ILC1, 2, and 3 showed a delayed increase in numbers corresponding to the contact hypersensitivity resolution phase. Hapten challenge induced increased marker cytokines in all ILC subtypes and an activated phenotype in ILC2. Depletion of all ILC resulted in a significantly enhanced ear swelling response. Similarly, ILC2-deficient mice (Rorasg/floxIl7rCre/+) displayed increased ear swelling responses on hapten challenge, suggesting that ILC2 act as negative regulators in the type 1-dominated immune response of contact hypersensitivity

Senescence-induced endothelial phenotypes underpin immune-mediated senescence surveillance.

Funder: National Institute for Health and Care ResearchFunder: Diabetes UKFunder: BIRAXSenescence is a stress-responsive tumor suppressor mechanism associated with expression of the senescence-associated secretory phenotype (SASP). Through the SASP, senescent cells trigger their own immune-mediated elimination, which if evaded leads to tumorigenesis. Senescent parenchymal cells are separated from circulating immunocytes by the endothelium, which is targeted by microenvironmental signaling. Here we show that SASP induces endothelial cell NF-κB activity and that SASP-induced endothelial expression of the canonical NF-κB component Rela underpins senescence surveillance. Using human liver sinusoidal endothelial cells (LSECs), we show that SASP-induced endothelial NF-κB activity regulates a conserved transcriptional program supporting immunocyte recruitment. Furthermore, oncogenic hepatocyte senescence drives murine LSEC NF-κB activity in vivo. Critically, we show two distinct endothelial pathways in senescence surveillance. First, endothelial-specific loss of Rela prevents development of Stat1-expressing CD4+ T lymphocytes. Second, the SASP up-regulates ICOSLG on LSECs, with the ICOS-ICOSLG axis contributing to senescence cell clearance. Our results show that the endothelium is a nonautonomous SASP target and an organizing center for immune-mediated senescence surveillance

Tissue-Restricted Adaptive Type 2 Immunity Is Orchestrated by Expression of the Costimulatory Molecule OX40L on Group 2 Innate Lymphoid Cells.

The local regulation of type 2 immunity relies on dialog between the epithelium and the innate and adaptive immune cells. Here we found that alarmin-induced expression of the co-stimulatory molecule OX40L on group 2 innate lymphoid cells (ILC2s) provided tissue-restricted T cell co-stimulation that was indispensable for Th2 and regulatory T (Treg) cell responses in the lung and adipose tissue. Interleukin (IL)-33 administration resulted in organ-specific surface expression of OX40L on ILC2s and the concomitant expansion of Th2 and Treg cells, which was abolished upon deletion of OX40L on ILC2s (Il7raCre/+Tnfsf4fl/fl mice). Moreover, Il7raCre/+Tnfsf4fl/fl mice failed to mount effective Th2 and Treg cell responses and corresponding adaptive type 2 pulmonary inflammation arising from Nippostrongylus brasiliensis infection or allergen exposure. Thus, the increased expression of OX40L in response to IL-33 acts as a licensing signal in the orchestration of tissue-specific adaptive type 2 immunity, without which this response fails to establish.ERC, EMB

Context-dependent effects of IL-2 rewire immunity into distinct cellular circuits.

Funder: Fondation pour l'Aide à la Recherche sur la Sclérose en PlaquesFunder: Alzheimer's AssociationFunder: European Research CouncilFunder: Fondation pour l’Aide à la Recherche sur la Sclérose en PlaquesFunder: VetenskapsrådetFunder: Alzheimer’s AssociationFunder: Fonds Wetenschappelijk OnderzoekFunder: Vlaams Instituut voor BiotechnologieInterleukin 2 (IL-2) is a key homeostatic cytokine, with therapeutic applications in both immunogenic and tolerogenic immune modulation. Clinical use has been hampered by pleiotropic functionality and widespread receptor expression, with unexpected adverse events. Here, we developed a novel mouse strain to divert IL-2 production, allowing identification of contextual outcomes. Network analysis identified priority access for Tregs and a competitive fitness cost of IL-2 production among both Tregs and conventional CD4 T cells. CD8 T and NK cells, by contrast, exhibited a preference for autocrine IL-2 production. IL-2 sourced from dendritic cells amplified Tregs, whereas IL-2 produced by B cells induced two context-dependent circuits: dramatic expansion of CD8+ Tregs and ILC2 cells, the latter driving a downstream, IL-5-mediated, eosinophilic circuit. The source-specific effects demonstrate the contextual influence of IL-2 function and potentially explain adverse effects observed during clinical trials. Targeted IL-2 production therefore has the potential to amplify or quench particular circuits in the IL-2 network, based on clinical desirability