ILC2-derived LIF licences progress from tissue to systemic immunity.

Migration and homing of immune cells are critical for immune surveillance. Trafficking is mediated by combinations of adhesion and chemokine receptors that guide immune cells, in response to chemokine signals, to specific locations within tissues and the lymphatic system to support tissue-localized immune reactions and systemic immunity1,2. Here we show that disruption of leukaemia inhibitory factor (LIF) production from group 2 innate lymphoid cells (ILC2s) prevents immune cells leaving the lungs to migrate to the lymph nodes (LNs). In the absence of LIF, viral infection leads to plasmacytoid dendritic cells (pDCs) becoming retained in the lungs where they improve tissue-localized, antiviral immunity, whereas chronic pulmonary allergen challenge leads to marked immune cell accumulation and the formation of tertiary lymphoid structures in the lung. In both cases immune cells fail to migrate to the lymphatics, leading to highly compromised LN reactions. Mechanistically, ILC2-derived LIF induces the production of the chemokine CCL21 from lymphatic endothelial cells lining the pulmonary lymphatic vessels, thus licensing the homing of CCR7+ immune cells (including dendritic cells) to LNs. Consequently, ILC2-derived LIF dictates the egress of immune cells from the lungs to regulate tissue-localized versus systemic immunity and the balance between allergen and viral responsiveness in the lungs.

The prognostic value of neutrophil-to-lymphocyte ratio across all stages of coronary artery disease.

The natural history of coronary heart disease (CAD) commonly begins with atherosclerosis, progressing to chronic coronary syndrome (CCS), acute coronary syndrome (ACS), and eventually, heart failure. Despite advancements in preventive and therapeutic strategies, there is room for further cardiovascular risk reduction. Recently, inflammation has emerged as a potential therapeutic target. The neutrophil-to-lymphocyte ratio (NLR) is a novel inflammatory biomarker which predicts poor prognosis in several conditions such as metabolic syndrome, sepsis, malignancy and CAD. In atherosclerosis, a high NLR predicts plaque vulnerability and severe stenosis. This is consistent with observations in CCS, where an elevated NLR predicts long-term major adverse cardiac events (MACEs). In ACS patients, high NLR levels are associated with larger infarct sizes and poor long-term outcomes. Possible reasons for this include failure of fibrinolysis, ischemia-reperfusion injury and in-stent restenosis, all of which are associated with raised NLR levels. Following myocardial infarction, an elevated NLR correlates with pathological cardiac remodeling which propagates chronic heart failure. Finally, in heart failure patients, an elevated NLR predicts long-term MACEs, mortality, and poor left ventricular assist device and transplant outcomes. Further studies must evaluate whether the addition of NLR to current risk-stratification models can better identify high-risk CAD patients.

Genome profiles of pathologist-defined cell clusters by multiregional LCM and G&T-seq in one triple-negative breast cancer patient.

Pathological examination is the gold standard for cancer diagnosis, and breast tumor cells are often found in clusters. We report a case study on one triple-negative breast cancer (TNBC) patient, analyzing tumor development, metastasis, and prognosis with simultaneous DNA and RNA sequencing of pathologist-defined cell clusters from multiregional frozen sections. The cell clusters are isolated by laser capture microdissection (LCM) from primary tumor tissue, lymphatic vessels, and axillary lymph nodes. Data are reported for a total of 97 cell clusters. A combination of tumor cell-cluster clonality and phylogeny reveals 3 evolutionarily distinct pathways for this patient, each associated with a unique mRNA signature, and each correlated with disparate survival outcomes. Hub gene analysis indicates that extensive downregulation of ribosomal protein mRNA is a potential marker of poor prognosis in breast cancer.

Self-Organizing Maps for Cellular In Silico Staining and Cell Substate Classification.

Cellular composition and structural organization of cells in the tissue determine effective antitumor response and can predict patient outcome and therapy response. Here we present Seg-SOM, a method for dimensionality reduction of cell morphology in H&E-stained tissue images. Seg-SOM resolves cellular tissue heterogeneity and reveals complex tissue architecture. We leverage a self-organizing map (SOM) artificial neural network to group cells based on morphological features like shape and size. Seg-SOM allows for cell segmentation, systematic classification, and in silico cell labeling. We apply the Seg-SOM to a dataset of breast cancer progression images and find that clustering of SOM classes reveals groups of cells corresponding to fibroblasts, epithelial cells, and lymphocytes. We show that labeling the Lymphocyte SOM class on the breast tissue images accurately estimates lymphocytic infiltration. We further demonstrate how to use Seq-SOM in combination with non-negative matrix factorization to statistically describe the interaction of cell subtypes and use the interaction information as highly interpretable features for a histological classifier. Our work provides a framework for use of SOM in human pathology to resolve cellular composition of complex human tissues. We provide a python implementation and an easy-to-use docker deployment, enabling researchers to effortlessly featurize digitalized H&E-stained tissue.

Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents.

We studied a child with severe viral, bacterial, fungal, and parasitic diseases, who was homozygous for a loss-of-function mutation of REL, encoding c-Rel, which is selectively expressed in lymphoid and myeloid cells. The patient had low frequencies of NK, effector memory cells reexpressing CD45RA (Temra) CD8+ T cells, memory CD4+ T cells, including Th1 and Th1*, Tregs, and memory B cells, whereas the counts and proportions of other leukocyte subsets were normal. Functional deficits of myeloid cells included the abolition of IL-12 and IL-23 production by conventional DC1s (cDC1s) and monocytes, but not cDC2s. c-Rel was also required for induction of CD86 expression on, and thus antigen-presenting cell function of, cDCs. Functional deficits of lymphoid cells included reduced IL-2 production by naive T cells, correlating with low proliferation and survival rates and poor production of Th1, Th2, and Th17 cytokines by memory CD4+ T cells. In naive CD4+ T cells, c-Rel is dispensable for early IL2 induction but contributes to later phases of IL2 expression. The patient's naive B cells displayed impaired MYC and BCL2L1 induction, compromising B cell survival and proliferation and preventing their differentiation into Ig-secreting plasmablasts. Inherited c-Rel deficiency disrupts the development and function of multiple myeloid and lymphoid cells, compromising innate and adaptive immunity to multiple infectious agents.

Prognostic value of platelet-to-lymphocyte ratio in neoadjuvant chemotherapy for solid tumors: A PRISMA-compliant meta-analysis.

INTRODUCTION: Previous research indicates that the platelet-to-lymphocyte ratio (PLR) may be an indicator of poor prognosis in many tumor types. However, the PLR is rarely described in patients undergoing neoadjuvant chemotherapy (NAC) for solid tumors. Thus, we performed a meta-analysis to investigate the prognostic value of this ratio for patients with solid tumors treated by NAC. METHODS: A comprehensive search of the literature was conducted using the PubMed, EMBASE, Cochrane Library, and Web of Science databases, followed by a manual search of references from the retrieved articles. Pooled hazard ratios (HRs) with 95% confidence interval (CIs) were used to evaluate the association between PLR and 3 outcomes, namely, overall survival, disease-free survival, and pathological complete response rate after NAC. RESULTS: Eighteen studies published no earlier than 2014 were included in our study. A lower PLR was associated with better overall survival (HR = 1.46, 95% CI, 1.11-1.92) and favorable disease-free survival (HR = 1.81, 95% CI, 1.27-2.59). A PLR that was higher than a certain cutoff was associated with a lower pathological complete response rate in patients with cancer who received NAC (Odds ratio = 1.93, 95% CI, 1.40-2.87). CONCLUSION: Elevated PLR is associated with poor prognosis in various solid tumors. PLR may be a useful biomarker in delineating those patients with poorer prognoses who may benefit from neoadjuvant therapies.

Progress and challenge for computational quantification of tissue immune cells.

Tissue immune cells have long been recognized as important regulators for the maintenance of balance in the body system. Quantification of the abundance of different immune cells will provide enhanced understanding of the correlation between immune cells and normal or abnormal situations. Currently, computational methods to predict tissue immune cell compositions from bulk transcriptomes have been largely developed. Therefore, summarizing the advantages and disadvantages is appropriate. In addition, an examination of the challenges and possible solutions for these computational models will assist the development of this field. The common hypothesis of these models is that the expression of signature genes for immune cell types might represent the proportion of immune cells that contribute to the tissue transcriptome. In general, we grouped all reported tools into three groups, including reference-free, reference-based scoring and reference-based deconvolution methods. In this review, a summary of all the currently reported computational immune cell quantification tools and their applications, limitations, and perspectives are presented. Furthermore, some critical problems are found that have limited the performance and application of these models, including inadequate immune cell type, the collinearity problem, the impact of the tissue environment on the immune cell expression level, and the deficiency of standard datasets for model validation. To address these issues, tissue specific training datasets that include all known immune cells, a hierarchical computational framework, and benchmark datasets including both tissue expression profiles and the abundances of all the immune cells are proposed to further promote the development of this field.

Admission Neutrophil-Lymphocyte Ratio (NLR) Predicts Survival in Patients with Extensive Burns.

BACKGROUND: Extensive burns is one of the most common severe injuries, with a high annual death rate. Previous studies showed that the neutrophil to lymphocyte ratio (NLR) is a prognostic factor for some inflammatory diseases. However, until now, no study has evaluated the clinical prognostic value of NLR in extensively burned patients. The aim of this study was to investigate the prognostic value of NLR in this medical condition to provide clinical guidance. METHODS: 271 patients diagnosed with extensive burns were analysed retrospectively between 2005 and 2018 in the Department of Burn Surgery of Changhai Hospital. NLR cut-off values at the first 3 days of hospitalization were calculated by the ROC analysis. RESULTS: Of the 271 patients in this study, the majority (82.3%) were injured by flame. The median total body surface area (TBSA) was 55% (IQR, 40% to 85%) and the median full thickness burn (FTB) was 20% (IQR, 3%-44%). The patients' NLR declined within the first 3 days after admission, and we found that NLR was negatively correlated with the ventilator-free days at day 28 (r = -0.127, P = 0.048). In a multivariate logistic regression analysis, higher admission NLR was independently predictive of higher mortality. According to the ROC curve, the best cut-off values for day 1 (or admission day), day 2 and day 3 NLR were 14, 13 and 7.5, respectively. We then performed a survival analysis, finding that those NLR above the cut-off point had decreased overall survival compared to those with NLR below the cut-off point (p = 0.023, 0.045 and 0.019 for day 1, 2, and 3, respectively). CONCLUSIONS: NLR continuously decreased in the first 3 days of hospitalization. Admission NLR above 14 is associated with a decreased survival in patients with extensive burns. These findings demonstrate that NLR has prognostic value in these patients.

Avaliação in vitro e in vivo do potencial imunomodulador de frações polissacarídicas extraídas do chuchu / In vitro and in vivo evaluation of the immunomodulatory potential of polysaccharide fractions extracted from chayote

Os polissacarídeos não amido constituem importante parcela das fibras dietéticas, e podem ser considerados modificadores de resposta biológica (MRBs), uma vez que são capazes de interagir com o sistema imune, e suas características estruturais estão atreladas aos efeitos biológicos gerados. O potencial imunomodulador dos polissacarídeos do chuchu já foi demonstrado, entretanto, informações sobre suas características estruturais e sua relação com o perfil imunológico são limitadas a ensaios in vitro, não havendo, até o momento, estudos in vivo. Assim, o objetivo do estudo foi avaliar, in vitro e in vivo, o perfil imunomodulador de frações isoladas do polissacarídeo do chuchu. Por meio da filtração tangencial foram obtidas as frações de estudo, SeRI<50 e SeSE<50, respectivamente as frações isoladas do polissacarídeo do chuchu extraídas do resíduo insolúvel e do sobrenadante pós-tratamento enzimático para retirada do amido com peso molecular menor que 50 kDa. A caracterização por meio da determinação da composição monossacarídica e da análise de ligação apontou que ambas as frações são formadas por galacturonanos, arabinanos, arabinogalactanos e glicomananos. A SeRI<50 é menos ramificada e, provavelmente, composta por galactanos, enquanto SeSE<50 é mais ramificada e, provavelmente, composta por galactuglucomananos. Essas frações foram capazes de estimular os macrófagos murinos RAW 264.7 e as células mononucleares do baço, do sangue e do intestino delgado de camundongos Balb/c, sugerindo um perfil de ação mais pró-inflamatório, com base nos efeitos produzidos pelas espécies reativas de oxigênio, citocinas e pelos marcadores de ativação de linfócitos. Ambas as amostras, SeRI<50 e SeSE<50, mostraram ser eficientes em ativar a cascata imunológica, não sendo citotóxicas mesmo com a maior concentração testada no ensaio in vitro

Non-starch polysaccharides are important components of dietary fibers, and they may be considered biological response modifiers (MRBs), as they may interact with the immune system, depending on their structural characteristics. The immunomodulatory potential of chayote polysaccharides has already been demonstrated, however, information on their structural characteristics and their relationship with the immunological profile are limited to in vitro assays, with no reports on in vivo studies. Thus, the objective of the study was to evaluate, in vitro and in vivo, the immunomodulatory profile of polysaccharide from chayote. Through tangential filtration two fractions, SeRI <50 and SeSE <50, were obtained, respectively the fraction isolated from the chayote polysaccharide extracted from the insoluble residue and the fraction from the enzymatic post-treatment supernatant to remove starch, both under molecular weight 50 kDa. The monosaccharide composition and linkage analysis showed that both fractions are formed by galacturonans, arabinans, arabinogalactans and glycomanans. SeRI <50 is less branched and probably composed of galactans, while SeSE <50 is more branched and probably composed of galactuglucomannans. These fractions were able to stimulate murine macrophages RAW 264.7 and mononuclear cells of the spleen, blood and small intestine of Balb / c mice, suggesting a more proinflammatory action profile, based on the reactive oxygen species production, cytokines and lymphocyte activation markers. Both samples, SeRI <50 and SeSE <50, were able to efficiently activate the immunological cascade, not being cytotoxic even at the highest concentration tested in the in vitro assay

Comprehensive mapping of the human cytokine gene regulatory network.

Proper cytokine gene expression is essential in development, homeostasis and immune responses. Studies on the transcriptional control of cytokine genes have mostly focused on highly researched transcription factors (TFs) and cytokines, resulting in an incomplete portrait of cytokine gene regulation. Here, we used enhanced yeast one-hybrid (eY1H) assays to derive a comprehensive network comprising 1380 interactions between 265 TFs and 108 cytokine gene promoters. Our eY1H-derived network greatly expands the known repertoire of TF-cytokine gene interactions and the set of TFs known to regulate cytokine genes. We found an enrichment of nuclear receptors and confirmed their role in cytokine regulation in primary macrophages. Additionally, we used the eY1H-derived network as a framework to identify pairs of TFs that can be targeted with commercially-available drugs to synergistically modulate cytokine production. Finally, we integrated the eY1H data with single cell RNA-seq and phenotypic datasets to identify novel TF-cytokine regulatory axes in immune diseases and immune cell lineage development. Overall, the eY1H data provides a rich resource to study cytokine regulation in a variety of physiological and disease contexts.

Leukocyte populations in peripheral blood of dromedary camels with clinical endometritis.

Endometritis represents the main cause of reproductive failure in dromedary camels. In dromedary camels, associations between endometritis-causing pathogen-species, disease severity, and systemic changes in the immune system have not been evaluated. In the current study, there was use of flow cytometry and immunofluorescence of membrane proteins for the evaluation of leukocyte subsets and the cellular phenotype in blood of camels with clinical endometritis and evaluations of associations with disease severity and endometritis-causing pathogens. Animals with endometritis had markedly larger numbers of total leukocytes and neutrophils. Although total lymphocyte and monocyte counts did not differ between camels with and without clinical endometritis, there were lesser numbers of total and effector CD4-positive T cells in camels with endometritis. Among monocytes, number of camel inflammatory monocytes (Mo-II) was markedly greater, whereas Mo-III numbers were less in the blood of camels with clinical endometritis. Number of inflammatory monocytes was also indicative of endometritis severity grade. Among camels with clinical endometritis, E. coli- and S. aureus-infected animals had similar endometritis grades and comparable phenotype and composition patterns of leukocytes. Neutrophils and monocytes of camels with clinical endometritis had fewer cell adhesion molecules (i.e., CD11a and CD18). Collectively, the results from the current study allowed for identification of associations between endometritis severity grade and larger numbers of inflammatory monocytes. The results also indicate there is no association between endometritis pathogen-species and changes in phenotype or composition of blood leukocytes.

High neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio predict poor survival in rectal cancer patients receiving neoadjuvant concurrent chemoradiotherapy.

This study explored the prognostic value of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in rectal cancer patients receiving neoadjuvant concurrent chemoradiotherapy (CCRT).Between January 2006 and December 2016, 184 patients with newly-diagnosed rectal cancer receiving neoadjuvant CCRT were enrolled. Risk of overall survival (OS) and disease-free survival (DFS) were calculated using the Kaplan-Meier method and Cox proportional hazard models. Stratified survival analyses were also performed between post-neoadjuvant pathological (yp) stage.The mean follow-up time was 72.73 ±â€Š36.82 months. High- and low-NLR patients differed significantly in both 5-year DFS (P = .026) and OS (P = .016). High- and low-PLR patients differed significantly in 5-year DFS (P = .011) but not OS (P = .185). Multivariate analyses revealed worse 5-year DFS (adjusted HR [aHR] = 2.8; 95% CI: 1.473-5.41; P = .002) and 5-year OS (aHR = 1.871; 95%CI: 1.029-3.4; P = .04) in the high-NLR group after adjusting for covariates. After adjustments, the high-PLR group had inferior 5-year DFS (aHR = 2.274; 95%CI: 1.473-5.419; P = .038) but not 5-year OS (aHR = 1.156; 95%CI: 0.650-2.056; P = .622). Further stratified analysis indicated that yp stage II and III patients with high NLR had worse 5-year DFS (aHR = 2.334; 95% CI: 1.158-4.725; P = .018) and OS (aHR = 2.226; 95% CI: 1.165-4.251; P = .015). Additionally, yp stage II and III patients with high PLR had inferior 5-year DFS (aHR = 2.012; 95% CI: 1.049-3.861; P = .036).Pre-CCRT NLR and PLR are independent prognostic factors for rectal cancer patients and could be used as a potential biomarker to identify high-risk patients for more intense treatment and care.

Does the preoperative platelet-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio predict morbidity after gastrectomy for gastric cancer?

BACKGROUND: Gastric cancer is the 2nd most common cause of cancer-related deaths, and the morbidity rate after surgery is reported to be as high as 46%. The estimation of possible complications, morbidity, and mortality and the ability to specify patients at high risk have become substantial for an intimate follow-up and for proper management in the intensive care unit. This study aimed to determine the prognostic value of the preoperative platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) and their relations with clinical outcomes and complications after gastrectomy for gastric cancer. METHODS: This single-center, retrospective cohort study evaluated the data of 292 patients who underwent gastrectomy with curative intent between January 2015 and June 2018 in a tertiary state hospital in Ankara, Turkey. A receiver operating characteristic curve was generated to evaluate the ability of laboratory values to predict clinically relevant postoperative complications. The area under the curve was computed to compare the predictive power of the NLR and PLR. Then, the cutoff points were selected as the stratifying values for the PLR and NLR. RESULTS: The area under the curve values of the PLR (0.60, 95% CI 0.542-0.657) and NLR (0.556, 95% CI 0.497-0.614) were larger than those of the other preoperative laboratory values. For the PLR, the diagnostic sensitivity and specificity were 50.00 and 72.22%, respectively, whereas for the NLR, the diagnostic sensitivity and specificity were 37.50 and 80.16%, respectively. The PLR was related to morbidity, whereas the relation of the NLR with mortality was more prominent. This study demonstrated that the PLR and NLR may predict mortality and morbidity via the Clavien-Dindo classification in gastric cancer patients. The variable was grade ≥ 3 in the Clavien-Dindo classification, including complications requiring surgical or endoscopic interventions, life-threatening complications, and death. Both the PLR and NLR differed significantly according to Clavien-Dindo grade ≥ 3. In this analysis, the PLR was related to morbidity, while the NLR relation with mortality was more intense. CONCLUSION: Based on the results of the study, the PLR and NLR could be used as independent predictive factors for mortality and morbidity in patients with gastric cancer.

Dynamic changes of innate lymphoid cells in acute ST-segment elevation myocardial infarction and its association with clinical outcomes.

An increasing body of evidence has implicated the innate immune system in the causation of acute ST-segment elevation myocardial infarction (STEMI). Innate lymphoid cells (ILCs) are newly identified members of the lymphoid lineage that are important effectors of innate immunity. The role of ILCs in STEMI has not been explored. We characterized the ILCs present in peripheral blood of 176 STEMI patients and 52 controls. Patients were followed up for up to 23 months. Flow cytometry showed that the proportion of total ILCs and ILC1s were significantly increased compared with controls; contrary to ILC1s, the proportion of ILC2s among total ILCs decreased significantly during the acute phase of STEMI. ILC1s percentage was an independent predictor of major adverse cardiovascular events (MACE). On multivariate Cox regression, the 3rd tertile of ILC1s was associated with a higher MACE rate compared with the 1st tertile (hazard ratio: 2.26; 95% confidence interval 1.56-3.27; P = 0.014). RNA-sequencing (RNA-Seq) revealed increased expressions of interferon-γ, tumor necrosis factor-α, vascular cell adhesion molecule 1 (VCAM1), and matrix metallopeptidase 9. Moreover, as active factors secreted by ILC1s, levels of interleukin (IL)-12 and IL-18 were significantly increased in STEMI patients. Increased ILC1s in patients with STEMI was associated with poor outcomes. Our findings suggest that ILC1s may play an important role in STEMI.

Group 3 innate lymphoid cells mediate early protective immunity against tuberculosis.

Tuberculosis is the leading cause of death by an infectious disease worldwide1. However, the involvement of innate lymphoid cells (ILCs) in immune responses to infection with Mycobacterium tuberculosis (Mtb) is unknown. Here we show that circulating subsets of ILCs are depleted from the blood of participants with pulmonary tuberculosis and restored upon treatment. Tuberculosis increased accumulation of ILC subsets in the human lung, coinciding with a robust transcriptional response to infection, including a role in orchestrating the recruitment of immune subsets. Using mouse models, we show that group 3 ILCs (ILC3s) accumulated rapidly in Mtb-infected lungs and coincided with the accumulation of alveolar macrophages. Notably, mice that lacked ILC3s exhibited a reduction in the accumulation of early alveolar macrophages and decreased Mtb control. We show that the C-X-C motif chemokine receptor 5 (CXCR5)-C-X-C motif chemokine ligand 13 (CXCL13) axis is involved in Mtb control, as infection upregulates CXCR5 on circulating ILC3s and increases plasma levels of its ligand, CXCL13, in humans. Moreover, interleukin-23-dependent expansion of ILC3s in mice and production of interleukin-17 and interleukin-22 were found to be critical inducers of lung CXCL13, early innate immunity and the formation of protective lymphoid follicles within granulomas. Thus, we demonstrate an early protective role for ILC3s in immunity to Mtb infection.

Type 3 ILCs in Lung Disease.

The lungs represent a complex immune setting, balancing external environmental signals with a poised immune response that must protect from infection, mediate tissue repair, and maintain lung function. Innate lymphoid cells (ILCs) play a central role in tissue repair and homeostasis, and mediate protective immunity in a variety of mucosal tissues, including the lung. All three ILC subsets are present in the airways of both mice and humans; and ILC2s shown to have pivotal roles in asthma, airway hyper-responsiveness, and parasitic worm infection. The involvement of ILC3s in respiratory diseases is less well-defined, but they are known to be critical in homeostasis, infection and inflammation at other mucosal barriers, such as the gut. Moreover, they are important players in the IL17/IL22 axis, which is key to lung health. In this review, we discuss the emerging role of ILC3s in the context of infectious and inflammatory lung diseases, with a focus on data from human subjects.

Runx/Cbfß complexes protect group 2 innate lymphoid cells from exhausted-like hyporesponsiveness during allergic airway inflammation.

Group 2 innate lymphoid cells (ILC2s) have tissue-resident competence and contribute to the pathogenesis of allergic diseases. However, the mechanisms regulating prolonged ILC2-mediated TH2 cytokine production under chronic inflammatory conditions are unclear. Here we show that, at homeostasis, Runx deficiency induces excessive ILC2 activation due to overly active GATA-3 functions. By contrast, during allergic inflammation, the absence of Runx impairs the ability of ILC2s to proliferate and produce effector TH2 cytokines and chemokines. Instead, functional deletion of Runx induces the expression of exhaustion markers, such as IL-10 and TIGIT, on ILC2s. Finally, these 'exhausted-like' ILC2s are unable to induce type 2 immune responses to repeated allergen exposures. Thus, Runx confers competence for sustained ILC2 activity at the mucosa, and contributes to allergic pathogenesis.