Journal articles on the topic 'Human ILC2 function'
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Lim, Ai Ing, Silvia Menegatti, Jacinta Bustamante, Lionel Le Bourhis, Matthieu Allez, Lars Rogge, Jean-Laurent Casanova, Hans Yssel, and James P. Di Santo. "IL-12 drives functional plasticity of human group 2 innate lymphoid cells." Journal of Experimental Medicine 213, no. 4 (March 14, 2016): 569–83. http://dx.doi.org/10.1084/jem.20151750.
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Group 2 innate lymphoid cells (ILC2) include IL-5– and IL-13–producing CRTh2+CD127+ cells that are implicated in early protective immunity at mucosal surfaces. Whereas functional plasticity has been demonstrated for both human and mouse ILC3 subsets that can reversibly give rise to IFN-γ–producing ILC1, plasticity of human or mouse ILC2 has not been shown. Here, we analyze the phenotypic and functional heterogeneity of human peripheral blood ILC2. Although subsets of human CRTh2+ ILC2 differentially express CD117 (c-kit receptor), some ILC2 surface phenotypes are unstable and can be modulated in vitro. Surprisingly, human IL-13+ ILC2 can acquire the capacity to produce IFN-γ, thereby generating plastic ILC2. ILC2 cultures demonstrated that IFN-γ+ ILC2 clones could be derived and were stably associated with increased T-BET expression. The inductive mechanism for ILC2 plasticity was mapped to the IL-12–IL-12R signaling pathway and was confirmed through analysis of patients with Mendelian susceptibility to mycobacterial disease due to IL-12Rβ1 deficiencies that failed to generate plastic ILC2. We also detected IL-13+IFN-γ+ ILC2 ex vivo in intestinal samples from Crohn’s disease patients. These results demonstrate cytokine production plasticity for human ILC2 and further suggest that environmental cues can dictate ILC phenotype and function for these tissue-resident innate effector cells.
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Surace, Laura, Jean-Marc Doisne, Carys A. Croft, Anna Thaller, Pedro Escoll, Solenne Marie, Natalia Petrosemoli, et al. "Dichotomous metabolic networks govern human ILC2 proliferation and function." Nature Immunology 22, no. 11 (October 22, 2021): 1367–74. http://dx.doi.org/10.1038/s41590-021-01043-8.
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AbstractGroup 2 innate lymphoid cells (ILC2s) represent innate homologs of type 2 helper T cells (TH2) that participate in immune defense and tissue homeostasis through production of type 2 cytokines. While T lymphocytes metabolically adapt to microenvironmental changes, knowledge of human ILC2 metabolism is limited, and its key regulators are unknown. Here, we show that circulating ‘naive’ ILC2s have an unexpected metabolic profile with a higher level of oxidative phosphorylation (OXPHOS) than natural killer (NK) cells. Accordingly, ILC2s are severely reduced in individuals with mitochondrial disease (MD) and impaired OXPHOS. Metabolomic and nutrient receptor analysis revealed ILC2 uptake of amino acids to sustain OXPHOS at steady state. Following activation with interleukin-33 (IL-33), ILC2s became highly proliferative, relying on glycolysis and mammalian target of rapamycin (mTOR) to produce IL-13 while continuing to fuel OXPHOS with amino acids to maintain cellular fitness and proliferation. Our results suggest that proliferation and function are metabolically uncoupled in human ILC2s, offering new strategies to target ILC2s in disease settings.
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Hurrell, Benjamin P., Doumet Goerges Helou, Pedram Shafiei-Jahani, Emily Diane Howard, Jacob Dean Painter, Christine Quach, and Omid Akbari. "CB2 engagement enhances group 2 innate lymphoid cell expansion and induction of airway hyperreactivity." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 109.14. http://dx.doi.org/10.4049/jimmunol.208.supp.109.14.
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Abstract Cannabinoids modulate the activation of immune cells and physiological processes in the lungs. Group 2 innate lymphoid cells (ILC2)s are central players in type-2 asthma, but how cannabinoids modulate ILC2 activation remains to be elucidated. Using a combination of cannabinoid receptor (CB)2 KO mice, a CB2 antagonist and agonist, we here provide evidence that CB2 signaling in ILC2s is important for the development of ILC2-driven airway inflammation in both mice and human. We show that both naïve and activated murine pulmonary ILC2s express CB2. CB2 signaling did not affect ILC2 homeostasis at steady state, but strikingly stimulated ILC2 proliferation and function upon activation using various models of airway inflammation including IL-33, IL-25 and Alternaria alternata. As a result, ILC2s lacking CB2 induced lower lung inflammation, as we made similar observations using a CB2 antagonist. Conversely, CB2 agonism remarkably exacerbated ILC2-driven airway hyperreactivity and lung inflammation. Mechanistically, transcriptomic and protein analysis revealed that CB2 signaling induced CREB phosphorylation in ILC2s. Human ILC2s expressed CB2, as CB2 antagonism and agonism showed opposing effects on ILC2 effector function and development of airway hyperreactivity in humanized mice. Collectively, our results define CB2 signaling in ILC2s as an important modulator of airway inflammation. Furthermore, our findings highlight the stimulatory capacity of cannabinoids on ILC2s and offer new therapeutic avenues, including the use of substances or pathways able to modulate CB2 and capable of alleviating lung function in patients with lung inflammation.
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Maazi, Hadi, Homayon Banie, German Aleman, Gavin Lewis, Nisheel Patel, Bowen Wang, Pejman Soroosh, and Omid Akbari. "Toll-like receptor-7-mediated activation of pDCs suppresses the ILC2-mediated airway hyperreactivity and inflammation through type-I interferon." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 53.7. http://dx.doi.org/10.4049/jimmunol.198.supp.53.7.
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Abstract Type 2 innate lymphoid cells (ILC2s) are newly identified subset of immune cells that play important roles in the pathogenesis of allergic diseases and asthma. The regulatory mechanisms that control the function and homeostasis of ILC2s are incompletely understood. Plasmacytoid dendritic cells (pDCs) have been previously associated with maintaining respiratory tolerance. To identify a novel mechanism for alleviating ILC2-mediated asthma we investigated impact of pDCs on ILC2s and ILC2-mediated airway hyperreactivity and inflammation. We investigated human and murine ILC2s and used clinically relevant allergen, Alternaria Alternata, as well as IL-33, to activate ILC2s in several mouse models including BDCA-2-DTR transgenic and Interferon alpha receptor-1 deficient mice. We found that activation of pDCS by a Toll-like receptor-7 agonist, R848, suppresses ILC2-mediated AHR and airway inflammation and that depletion of pDCs reverses this suppression. Moreover, we found that pDCs suppress cytokine production and proliferation of ILC2s through the production of interferon alpha. Transcriptome analysis of both human and murine ILC2s confirms the activation of regulatory pathways in ILC2s by interferon alpha. In addition, activation of pDCs alleviates airway hyperreactivity and inflammation by suppressing ILC2’s function and survival. Our findings reveal a novel regulatory pathway in ILC2-mediated pulmonary inflammation with important clinical implications.
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Hurrell, Benjamin P., Lauriane Galle-Treger, Pedram Shafiei Jahani, Emily Howard, Doumet Georges Helou, Homayon Banie, Pejman Soroosh, and Omid Akbari. "TNFR2 signaling enhances ILC2 survival, function and induction of airway hyperreactivity." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 60.5. http://dx.doi.org/10.4049/jimmunol.204.supp.60.5.
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Abstract Group 2 innate lymphoid cells (ILC2s) can initiate pathologic inflammation in allergic asthma by secreting copious amounts of type-2 cytokines, promoting lung eosinophilia and airway hyperreactivity (AHR), a cardinal feature of asthma. We discovered that the TNF/TNFR2 axis is a central immune checkpoint in murine and human ILC2s. TNFa is a pleiotropic proinflammatory cytokine which is elevated in the airways of patients with severe asthma, signaling through two main receptors with opposing functions: TNFR1 and TNFR2. We found that murine ILC2s selectively express and induce TNFR2 upon IL-33 activation, whereas they fail to express – or induce – TNFR1. Strikingly, blocking the TNF/TNFR2 axis inhibits ILC2 survival, cytokine production, ILC2-dependent AHR and airway eosinophilia. The mechanism of action of TNFR2 in ILC2s is through utilizing non-canonical NFkB pathway as a NFkB inducing kinase (NIK) inhibitor blocks the costimulatory effects of TNFa both in vitro and in vivo. Similarly, human ILC2s selectively express TNFR2 and using the model of humanized mice that our laboratory recently developed, we show that TNFR2 engagement in human ILC2s enhances survival and activation, ultimately promoting AHR through a NIK-dependent pathway. These findings highlight the role of the TNF/TNFR2 axis in pulmonary ILC2s, suggesting that targeting TNFR2 or relevant signaling represents a novel strategy for treating patients with ILC2-dependent asthma.
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Jowett, G. M., E. Read, M. D. Norman, P. A. Arevalo, M. Vilà González, L. Roberts, L. Vallier, et al. "OP13 Mucosal organoids capture Innate Lymphoid Cells (ILC) tissue-specific development and reveal that Inflammatory Bowel Disease-associated ILC modulate intestinal remodelling." Journal of Crohn's and Colitis 15, Supplement_1 (May 1, 2021): S013—S014. http://dx.doi.org/10.1093/ecco-jcc/jjab075.012.
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Abstract Background Innate Lymphoid Cells (ILC) develop from Common Lymphoid Precursors in the bone marrow, and ILC precursors (ILCP) migrate to mucosa where they mature, promote homeostasis, and provide a potent, antigen-non-specific sources of cytokines. Deciphering what local stimuli drive the final stages of ILCP maturation in these tissues remains a pressing question, as ILC frequencies can become dysregulated during chronic infection and inflammatory diseases. For example, Type-1 innate lymphoid cells (ILC1) are enriched in the mucosa of patients with active inflammatory bowel disease (IBD) and the impact of this accumulation remains elusive. Methods Here, we develop and use co-cultures of both murine and human iPSC-derived gut and lung organoids with ILCP and with mature ILC isolated from IBD patients’ intestinal biopsies. Results Harnessing these versatile models, we demonstrate that epithelial cells provide a complex niche capable of supporting the final maturation of all helper-like ILC1, ILC2, and ILC3. Notably, organoid identity was sufficient to robustly recapitulate tissue-specific ILC imprints and frequencies, even in the absence of microbial stimuli, other cell types, or cytokine supplementation. In addition, we show that that ILC1 drive expansion of the epithelial stem cell crypt through p38γ phosphorylation, driving a potentially pathological proliferative feedback loop between β-catenin and Cd44v6. We harnessed this model to elucidate that this phenotype was unexpectedly regulated by ILC1-derived TGFβ1. We further show that human gut ILC1 also secrete TGFβ1, and drive CD44v6 expression in both HIO epithelium and mesenchyme. As TGFβ1 is a master regulator of fibrosis, the leading indicator for surgery in IBD, we next characterised the ability of ILC1 to regulate matrix remodelling using a functionalized, synthetic hydrogel system. We show that ILC1 drive both matrix stiffening and degradation, which we posit occurs through a balance of MMP9 degradation and TGFβ1-induced fibronectin deposition. Conclusion Taken together, our work provides unprecedented insight into in situ ILC maturation, which we show to be driven by epithelial signals, and into ILC function. We also report that intestinal ILC1 modulate epithelial and matrix remodelling, which may drive either wound healing in homeostasis, but may tip toward pathology when enriched in IBD. Moreover, our work introduces a modular organoid platform, which provides exquisite control over both environmental stimuli and host genetics, making it a powerful tool for dissecting the interactions between complex mucosal tissues and rare cell subtypes in development and disease.
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Galle, Lauriane, Ishwarya Sankaranarayanan, Benjamin P. Hurrell, Emily Howard, Richard Lo, Hadi Maazi, Gavin Lewis, et al. "Costimulation of type-2 innate lymphoid cells by GITR promotes effector function and ameliorates type 2 diabetes." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 122.10. http://dx.doi.org/10.4049/jimmunol.202.supp.122.10.
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Abstract Metabolic syndrome is characterized by disturbances in glucose homeostasis and the development of low-grade systemic inflammation, which increase the risk to develop type-2 diabetes mellitus (T2DM). Type-2 innate lymphoid cells (ILC2s) are a recently discovered immune population secreting Th2-cytokines. While previous studies show how ILC2s can play a critical role in the regulation of metabolic homeostasis in the adipose tissue, a therapeutic target capable of modulating ILC2 activation has yet to be identified. We found that GITR, a member of the TNF superfamily, is expressed on murine adipose tissue ILC2s and its engagement on activated ILC2s induces Th2-cytokine secretion. Moreover, we showed that GITR engagement on ILC2s improves glucose homeostasis resulting in both protection against insulin-resistance onset and amelioration of established insulin-resistance. Our adoptive transfer studies demonstrated that this protective effect is dependent on ILC2-derived Th2-cytokines, particularly IL-13. Transcriptome analysis demonstrated that GITR agonist activates the NF-κB signaling pathway and inhibits ILC2 apoptosis, altogether favoring ILC2 survival and activation. Finally, we also found that GITR is expressed on human adipose tissue resident ILC2s and GITR engagement robustly induces Th2-cytokine. Together, these results highlight the critical role of GITR as a novel therapeutic molecule against T2DM and its fundamental role as an immune checkpoint for activated ILC2s.
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Kovats, Susan, Sean Turner, Anna Karlik, Reegan Miller, Erola Ainsua-Enrich, and Sapana Kadel. "Androgen receptor activity underlies sex differences in lung-resident ILC2 functional responses during influenza virus infection." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 85.4. http://dx.doi.org/10.4049/jimmunol.204.supp.85.4.
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Abstract Lung-resident group 2 innate lymphoid cells (ILC2s) produce type 2 cytokines and facilitate tissue repair in response to alarmins such as IL-33 released during respiratory virus infection, but they also may be functionally suppressed by type 1 cytokines. Lung ILC2s express notably high levels of intracellular androgen receptor (AR) compared to ILC1s, T and B cells. To test the hypothesis that females and males show differential ILC2 responses in influenza virus (IAV) infection, we analyzed the numbers and functional responses of lung ILCs in IAV infected mice. On days 3–10 post-infection, lungs of female mice contained greater numbers of ILC2s and ILC1s compared to males. However, the female ILC2s were preferentially suppressed at the peak of infection, with a dampened type 2 program manifest as attenuated proliferation, decreased IL-5 and amphiregulin production, reduced expression of GATA-3 and IL-33R and increased surface IFNGR. IFNG levels in the lung were comparable between sexes at day 7 post-infection, suggesting intrinsic differences in ILC2 responses to interferons. Indeed, naïve female ILC2s showed higher expression of IFNGR and higher phospho-STAT1 levels following stimulation by IFNG. ILC2s in naive male mice with lymphocyte-restricted AR deficiency displayed levels of IFNGR comparable to female mice, suggesting AR activity underlies sex differences in intrinsic IFNGR expression. Early life orchiectomy revealed that endogenous androgens decreased ILC2 numbers but protected males from suppression of ILC2s in IAV infection. Taken together, our data show that AR activity preserves canonical ILC2 function in males during IAV infection and may help to explain the documented human gender differences in immunity to IAV.
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Valdez, Yanet, Stephen K. Kyei, Grace F. T. Poon, Fumio Takei, Carrie Peters, Steve M. Woodside, Allen C. Eaves, and Terry E. Thomas. "Fast and efficient enrichment of functional ILC2 from human whole blood." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 209.16. http://dx.doi.org/10.4049/jimmunol.196.supp.209.16.
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Abstract Group 2 innate lymphoid cells (ILC2) are a functionally distinct subset of recently identified immune cells with important roles in type-2 immunopathologies such as allergies, asthma, helminth infections and other metabolic diseases. Studying these rare cells is challenging due to a lack of specific surface markers, and currently multicolor flow cytometric analysis and cell sorting are the only methods to characterize and isolate ILC2s. However, the scarcity of these cells makes flow cytometry time-consuming, expensive and often results in low purities and recoveries. Thus, better approaches for effective identification and isolation are essential to further understanding of ILC2 biology and function. We have developed a rapid and efficient method for enrichment of human ILC2 from whole blood. In brief, non-ILC2 cells in whole blood were crosslinked to red blood cells already present in the sample using RosetteSep™. The sample was then layered over Lymphoprep in a SepMate™ tube, spun at 1200 x g for 10 minutes (min), and the untouched, desired cells simply poured off. Cells were washed once and were then ready for subsequent analysis. Starting with only 0.01 – 0.07% in whole blood, ILC2 were enriched 350 ± 220 fold to 8.2 ± 6.8% in 35 min (means ± SD, n=17). Subsequent cell sorting from these pre-enriched samples was faster and yielded higher purity ILC2 than sorting from non-enriched controls (n=3, p<0.05 paired t test). Sorted ILC2, both pre-enriched and non-enriched controls, were cultured and stimulated, and secreted similar high levels of IL-13 as assessed by ELISA, indicating that these cells are functional. In summary, ILC2 pre-enrichment improves sorting efficiency, increases ILC2 purity, and maintains ILC2 functionality.
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Maazi, Hadi, Nisheel Patel, Ishwarya Sankaranarayanan, Diamanda Riagas, Pejman Soroosh, Gordon Freeman, Arlene Sharpe, and Omid Akbari. "ICOS: ICOS-ligand interaction is essential for ILC2 function and survival (HYP2P.322)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 53.3. http://dx.doi.org/10.4049/jimmunol.194.supp.53.3.
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Abstract Type 2 Innate lymphoid cells (ILC2s) are a newly identified subset of immune cells that play important roles in the pathogenesis of allergic asthma by producing large amounts of IL-5 and IL-13. ILC2 lack lineage markers but express CD45, IL-2Rα, IL-33R and IL-7Rα. All murine ILC2s and a significant portion of human ILC2s express Inducible T-cell COStimulator (ICOS) that is essential for T cell activation and function, however, the role of ICOS in ILC2s remains unknown. We investigated the role of ICOS in the function and survival of murine and human ILC2s using ICOS-/- and RAG2-/- and humanized mice in different experimental setups. We found that:1) ICOS-/- mice show lower IL-33-induced airway hyperreactivity (AHR) and eosinophilia than wild type (WT) mice. 2) Survival and the number of ILC2s is substantially lower in ICOS-/- than WT mice. 3) Blocking anti-ICOS antibody reduces survival and the number of ILC2s in WT mice. 4) Ex vivo stimulated ICOS-/- ILC2s show impaired IL-5 and IL-13 production compared to WT ILC2s. 5) Human peripheral ILC2s express ICOS and blocking ICOS:ICOS-Ligand interaction impairs their IL-5 and IL-13 production in vitro and IL-33 induced AHR and eosinophilia in humanized mice. 6) Human and murine ILC2s express ICOS-Ligand. 7) ICOS signaling modulates STAT5 pathway. Our results indicate that ICOS is required for the optimal function and survival of ILC2s and can be a novel therapeutic target in patients with ILC2-mediated asthma and lung inflammation.
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Drake, Li Y., Kay Bachman, and Hirohito Kita. "The function of the circulating innate lymphoid cells is dysregulated in patients with mild asthma." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 119.27. http://dx.doi.org/10.4049/jimmunol.202.supp.119.27.
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Abstract Group 2 innate lymphoid cells (ILC2s) play crucial roles in type 2 immunity in the lungs and in the development of asthma pathology. While ILC2s are residents in mucosal tissues, they also circulate in peripheral blood. Evidence suggests that blood ILC2s can be used as an indirect but useful biomarker to monitor the activity of ILC2s in mucosal tissues, such as the lungs. To investigate both the innate immune response and the corresponding ILC2 cell levels in the peripheral blood of asthma patients, we collected peripheral blood mononuclear cells (PBMCs) from 11 adult patients with mild asthma (MA) and 12 adult healthy control (HC) subjects. The innate type 2 immune responses of PBMCs and the number of blood ILC2s were examined by in vitro culture and flow cytometry. We found that in response to IL-25 or IL-33 stimulation, PBMCs from MA subjects produced significant higher levels of IL-5 than PBMCs from HC subjects. However, there were no significant differences in ILC2 numbers or proportions between MA and HC groups. These results suggest that the function, but not the number, of blood ILC2s may serve as a general biomarker for human asthma.
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Hardman, Clare S., Yi-Ling Chen, Maryam Salimi, Janina Nahler, Daniele Corridoni, Marta Jagielowicz, Chathuranga L. Fonseka, et al. "IL-6 effector function of group 2 innate lymphoid cells (ILC2) is NOD2 dependent." Science Immunology 6, no. 59 (May 21, 2021): eabe5084. http://dx.doi.org/10.1126/sciimmunol.abe5084.
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Cutaneous group 2 innate lymphoid cells (ILC2) are spatially and epigenetically poised to respond to barrier compromise and associated immunological threats. ILC2, lacking rearranged antigen-specific receptors, are primarily activated by damage-associated cytokines and respond with type 2 cytokine production. To investigate ILC2 potential for direct sensing of skin pathogens and allergens, we performed RNA sequencing of ILC2 derived from in vivo challenged human skin or blood. We detected expression of NOD2 and TLR2 by skin and blood ILC2. Stimulation of ILC2 with TLR2 agonist alone not only induced interleukin-5 (IL-5) and IL-13 expression but also elicited IL-6 expression in combination with Staphylococcus aureus muramyl dipeptide (MDP). Heat-killed skin-resident bacteria provoked an IL-6 profile in ILC2 in vitro that was notably impaired in ILC2 derived from patients with nucleotide-binding oligomerization domain-containing protein 2 (NOD2) mutations. In addition, we show that NOD2 signaling can stimulate autophagy in ILC2, which was also impaired in patients with NOD2 mutations. Here, we have identified a role for ILC2 NOD2 signaling in the differential regulation of ILC2-derived IL-6 and have reported a previously unrecognized pathway of direct ILC2 bacterial sensing.
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Blomme, Evy E., Sharen Provoost, Erica Bazzan, Hannelore P. Van Eeckhoutte, Mirjam P. Roffel, Lore Pollaris, Annelies Bontinck, et al. "Innate lymphoid cells in isocyanate-induced asthma: role of microRNA-155." European Respiratory Journal 56, no. 3 (June 4, 2020): 1901289. http://dx.doi.org/10.1183/13993003.01289-2019.
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BackgroundOccupational asthma, induced by workplace exposures to low molecular weight agents such as toluene 2,4-diisocyanate (TDI), causes a significant burden to patients and society. Little is known about innate lymphoid cells (ILCs) in TDI-induced asthma. A critical regulator of ILC function is microRNA-155, a microRNA associated with asthma.ObjectiveTo determine whether TDI exposure modifies the number of ILCs in the lung and whether microRNA-155 contributes to TDI-induced airway inflammation and hyperresponsiveness.MethodsC57BL/6 wild-type and microRNA-155 knockout mice were sensitised and challenged with TDI or vehicle. Intracellular cytokine expression in ILCs and T-cells was evaluated in bronchoalveolar lavage (BAL) fluid using flow cytometry. Peribronchial eosinophilia and goblet cells were evaluated on lung tissue, and airway hyperresponsiveness was measured using the forced oscillation technique. Putative type 2 ILCs (ILC2) were identified in bronchial biopsies of subjects with TDI-induced occupational asthma using immunohistochemistry. Human bronchial epithelial cells were exposed to TDI or vehicle.ResultsTDI-exposed mice had higher numbers of airway goblet cells, BAL eosinophils, CD4+ T-cells and ILCs, with a predominant type 2 response, and tended to have airway hyperresponsiveness. In TDI-exposed microRNA-155 knockout mice, inflammation and airway hyperresponsiveness were attenuated. TDI exposure induced IL-33 expression in human bronchial epithelial cells and in murine lungs, which was microRNA-155 dependent in mice. GATA3+CD3− cells, presumably ILC2, were present in bronchial biopsies.ConclusionTDI exposure is associated with increased numbers of ILCs. The proinflammatory microRNA-155 is crucial in a murine model of TDI asthma, suggesting its involvement in the pathogenesis of occupational asthma due to low molecular weight agents.
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Bartemes, Kathleen, Stephanie Fox, and Hirohito Kita. "IL-33- and IL-25-responsive innate lymphoid cells are present in human peripheral blood. (P6237)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 181.1. http://dx.doi.org/10.4049/jimmunol.190.supp.181.1.
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Abstract Recent advances in the initiation and maintenance of type 2 immune responses have highlighted a new cell type, the type 2 innate lymphoid cell (ILC2). Studies using mouse models show that ILC2s mediate helminth clearance in the gut and development of airway hyperresponsiveness in the lung. Further, the epithelium-derived cytokines IL-25 and IL-33 are integral to this process. However, how ILC2s contribute to chronic human airway diseases such as asthma and how IL-25 and IL-33 mediate that effect are not well characterized. Here we show that human peripheral blood mononuclear cells (PBMCs) respond to IL-33 or IL-25 stimulation by making IL-5 and IL-13. CD3+ and CD16+ PBMCs are not required. Furthermore, an ILC2-like cell that is lineage-negative and CD44+CD127+ST2+ is present in the peripheral blood of a subject with asthma. IL-5 production was induced by IL-33 or IL-25 in PBMCs from normal individuals as well as from patients with allergic rhinitis or allergic asthma, however, PBMCs from the group with asthma released significantly higher amounts. Our data suggests that the number and function of ILC2s is greater in patients with allergic asthma than in healthy subjects or patients with allergic rhinitis. Thus, ILC2s may be involved in the development of type 2 airway diseases.
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Wang, Yuan Min, Karli Shaw, Geoff Yu Zhang, Edmund Y. M. Chung, Min Hu, Qi Cao, Yiping Wang, et al. "Interleukin-33 Exacerbates IgA Glomerulonephritis in Transgenic Mice Overexpressing B Cell Activating Factor." Journal of the American Society of Nephrology 33, no. 5 (April 6, 2022): 966–84. http://dx.doi.org/10.1681/asn.2021081145.
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BackgroundThe cytokine IL-33 is an activator of innate lymphoid cells 2 (ILC2s) in innate immunity and allergic inflammation. B cell activating factor (BAFF) plays a central role in B cell proliferation and differentiation, and high levels of this protein cause excess antibody production, including IgA. BAFF-transgenic mice overexpress BAFF and spontaneously develop glomerulonephritis that resembles human IgA nephropathy.MethodsWe administered IL-33 or PBS to wild-type and BAFF-transgenic mice. After treating Rag1-deficient mice with IL-33, with or without anti-CD90.2 to preferentially deplete ILC2s, we isolated splenocytes, which were adoptively transferred into BAFF-transgenic mice.ResultsBAFF-transgenic mice treated with IL-33 developed more severe kidney dysfunction and proteinuria, glomerular sclerosis, tubulointerstitial damage, and glomerular deposition of IgA and C3. Compared with wild-type mice, BAFF-transgenic mice exhibited increases of CD19+ B cells in spleen and kidney and ILC2s in kidney and intestine, which were further increased by administration of IL-33. Administering IL-33 to wild-type mice had no effect on kidney function or histology, nor did it alter the number of ILC2s in spleen, kidney, or intestine. To understand the role of ILC2s, splenocytes were transferred from IL-33–treated Rag1-deficient mice into BAFF-transgenic mice. Glomerulonephritis and IgA deposition were exacerbated by transfer of IL-33–stimulated Rag1-deficient splenocytes, but not by ILC2 (anti-CD90.2)–depleted splenocytes. Wild-type mice infused with IL-33–treated Rag1-deficient splenocytes showed no change in kidney function or ILC2 numbers or distribution.ConclusionsIL-33–expanded ILC2s exacerbated IgA glomerulonephritis in a mouse model. These findings indicate that IL-33 and ILC2s warrant evaluation as possible mediators of human IgA nephropathy.
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Helou, Georges Doumet, Pedram Shafiei-Jahani, Richard Lo, Emily Diane Howard, Benjamin P. Hurrell, Lauriane Galle-Treger, Jacob Dean Painter, et al. "PD-1 agonist modulates ILC2 metabolism and ameliorates airway hyperreactivity." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 109.15. http://dx.doi.org/10.4049/jimmunol.208.supp.109.15.
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Abstract Allergic asthma is a chronic inflammatory disease characterized by airway hyperreactivity (AHR) and type-2 immune response. Type-2 innate lymphoid cells (ILC2s) mimic T helper 2 (Th2) cells in cytokine secretion and are among the first pulmonary immune responders to the allergen-induced alarmins. Programmed cell death protein-1 (PD-1) is known as an immune checkpoint equipped with tyrosine-based inhibitory motifs in the cytoplasmic tail. Since PD-1 is associated with immune regulation in many inflammatory diseases, the objective of this study was to investigate the role of PD-1 in the initiation and development of AHR. Lung function tests, RNA sequencing, flow cytometry, targeted metabolomic assays, and adoptive transfer experiments were principally used to explore the role of PD-1 in AHR mouse models and in human ILC2s. Using IL-33 and Alternaria alternata models, we have demonstrated that PD-1 knockout mice develop a higher AHR and lung inflammation as compared to control wild-type mice. In particular, PD-1 is highly inducible on lung ILC2s and downregulates their effector functions. Moreover, PD-1 controls glycolysis and methionine catabolism, limiting, therefore, the proliferation of activated pulmonary ILC2s. In line with mice data, PD-1 is inducible and functional in human ILC2s in response to IL-33. To confirm the translational relevance of our findings, we tested a novel human PD-1 agonist in vitro and in a humanized mouse model of AHR. Interestingly, the PD-1 agonist decreases human ILC2 activation and is able to dampen AHR and lung inflammation. Altogether this study reveals the protective role of PD-1 as regulators of ILC2s and highlights for the first time the therapeutic potential of PD-1 agonists in allergic asthma. Supported by grants from NIH: R01 ES025786, R01 ES021801, R01 HL144790, and R21 AI109059 (O.A.)
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van der Ploeg, Esmee K., Ana Carreras Mascaro, Danny Huylebroeck, Rudi W. Hendriks, and Ralph Stadhouders. "Group 2 Innate Lymphoid Cells in Human Respiratory Disorders." Journal of Innate Immunity 12, no. 1 (February 6, 2019): 47–62. http://dx.doi.org/10.1159/000496212.
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Recent studies using animal models have generated profound insight into the functions of various subsets of innate lymphoid cells (ILCs). The group 2 ILC subset (ILC2) has been implicated in tissue homeostasis, defense responses against parasites, tissue repair, and immunopathology associated with type-2 immunity. In addition, progress has also been made in translating these findings from animal studies into a context of human immunity. Importantly, recent observations strongly support a role for ILC2s in several diseases of the human respiratory system. However, many aspects of human ILC2 biology are still unclear, including how these cells develop and which signals control their activity. As a result, the exact role played by ILCs in human health and disease remains poorly understood. Here, we summarize our current understanding of human ILC2 biology and focus on their potential involvement in various human respiratory disorders.
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Konya, Viktoria, and Jenny Mjösberg. "Lipid mediators as regulators of human ILC2 function in allergic diseases." Immunology Letters 179 (November 2016): 36–42. http://dx.doi.org/10.1016/j.imlet.2016.07.006.
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Mazzurana, Luca, Marianne Forkel, Anna Rao, Aline Van Acker, Efthymia Kokkinou, Tamaki Ichiya, Sven Almer, Charlotte Höög, Danielle Friberg, and Jenny Mjösberg. "Suppression of Aiolos and Ikaros expression by lenalidomide reduces human ILC3–ILC1/NK cell transdifferentiation." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 187.10. http://dx.doi.org/10.4049/jimmunol.202.supp.187.10.
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Abstract The Ikaros family of transcription factors (TFs) are important regulators of lymphocyte function. However, their roles in human innate lymphoid cell (ILC) function remain unclear. Here, we found that Ikaros (IKZF1) is expressed by all ILC subsets, including NK cells, in blood, tonsil and gut, while Helios (IKZF2) is preferentially expressed by ILC3 in tonsil and gut. Aiolos (IKZF3) followed the expression pattern of T-bet and Eomes, being predominantly expressed by ILC1 and NK cells. Differentiation of IFN-γ-producing ILC1 and NK cells from ILC3 by IL-1β plus IL-12-stimulation was associated with upregulation of T-bet and Aiolos. Selective degradation of Aiolos and Ikaros by lenalidomide suppressed ILC1 and NK cell differentiation and expression of ILC1 and NK cell-related transcripts (LEF1, PRF1, GRZB, CD244, NCR3, IRF8). In line with reduced ILC1/NK cell differentiation we observed an increase in the expression of the ILC3-related TF Helios, as well as ILC3 transcripts (TNFSF13B, IL22, NRP1 and RORC) and in the frequency of IL-22 producing ILC3 in cultures with IL-1β and IL-23. These data suggest that suppression of Aiolos and Ikaros expression inhibits ILC1 and NK cell differentiation while ILC3 function is maintained. Hence, our results open up for new possibilities in targeting Ikaros family TFs for modulation of type 1/3 immunity in inflammation and cancer.
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Sui, Pengfei, Darin L. Wiesner, Jinhao Xu, Yan Zhang, Jinwoo Lee, Steven Van Dyken, Amber Lashua, et al. "Pulmonary neuroendocrine cells amplify allergic asthma responses." Science 360, no. 6393 (March 29, 2018): eaan8546. http://dx.doi.org/10.1126/science.aan8546.
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Pulmonary neuroendocrine cells (PNECs) are rare airway epithelial cells whose function is poorly understood. Here we show that Ascl1-mutant mice that have no PNECs exhibit severely blunted mucosal type 2 response in models of allergic asthma. PNECs reside in close proximity to group 2 innate lymphoid cells (ILC2s) near airway branch points. PNECs act through calcitonin gene-related peptide (CGRP) to stimulate ILC2s and elicit downstream immune responses. In addition, PNECs act through the neurotransmitter γ-aminobutyric acid (GABA) to induce goblet cell hyperplasia. The instillation of a mixture of CGRP and GABA in Ascl1-mutant airways restores both immune and goblet cell responses. In accordance, lungs from human asthmatics show increased PNECs. These findings demonstrate that the PNEC-ILC2 neuroimmunological modules function at airway branch points to amplify allergic asthma responses.
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Dulson, Sarah J., and Laurie E. Harrington. "STAT4 is required for protective Innate Lymphoid Cell responses to gastrointestinal infection." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 131.1. http://dx.doi.org/10.4049/jimmunol.198.supp.131.1.
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Abstract Innate Lymphoid Cells (ILCs) are a newly discovered subset of cells that serve both protective and pathogenic roles in intestinal health. ILCs consist of three defined subgroups and perform effector functions similar to CD4 T cells. However, ILCs lack a specific antigen receptor and are activated directly by cytokines early during an immune response. Since the initial events in an immune response can dictate the ability of the host to control intestinal infection, it is critical to identify molecules that regulate ILC function. Signal transducer and activator of transcription 4 (STAT4) is important for driving many pro-inflammatory responses and phenotypes in T cells, but its effects on ILC development and function remain unclear. Contrary to its known role in Th1 cell biology, we find STAT4 to be dispensable in Group 1 ILC (ILC1) development. However, we observe that STAT4 is critical for IFN-γ production by ILC1s, thus influencing the capacity of this subgroup to mount an effector response. Whereas STAT4 deficiency did not impact IL-22 or IL-17 production by ILC3s, the transcription factor specifically modulates IFNγ production by a plastic Tbet+ subgroup of ILC3s that is greatly expanded in response to inflammation. Importantly, STAT4 signaling is also critical for survival against a genetically modified strain of Listeria monocytogenes that is able to model human Listeriosis in mice. Furthermore, both ILC1 and ILC3 respond to infection with robust IFNγ production, and when ILCs are depleted mice are unable to mount a protective innate response and succumb earlier to infection. These results indicate that STAT4 signaling influences critical responses by ILCs, thereby contributing to host protection against intestinal infection.
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Cheepsattayakorn, Attapon, and Ruangrong Cheepsattayakorn. "Pulmonary pathology of COVID-19." Journal of Lung, Pulmonary & Respiratory Research 7, no. 3 (November 4, 2020): 79–83. http://dx.doi.org/10.15406/jlprr.2020.07.00234.
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Currently, animal-to-human transmission of SARS-CoV-2 (COVID-19) has not yet been confirmed, whereas the main mode of transmission is human-to-human. Droplets are the main route of human-to-human transmission, whereas aerosols could be another route in addition to stool-based transmission. Currently, no evidence is available to indicate intrauterine vertical transmission of SARS-CoV-2 (COVID-19) in pregnant women. In the host, the life cycle of coronavirus consists of 5 steps: 1) attachment, 2) penetration, 3) biosynthesis, 4) maturation, and 5) release. Once viruses bind to host receptors (attachment), they enter host cells, particularly type II pneumocytes via endocytosis or membrane fusion (penetration). Once viral contents are released inside the host cells, viral RNA enters the host’s nucleus for replication and making viral proteins (biosynthesis). New viral particles are produced (maturation) and released. Spike protein of coronaviruses which determines the diversity of coronaviruses and host tropism is composed of a transmembrane trimetric glycoprotein protruding from the viral surface. Structural and functional studies demonstrated that the spike protein the of coronaviruses can bind to angiotensin converting enzyme 2 (ACE2), a functional receptor for SARS-CoV. ACE2 expression is high in lung (high expression on lung epithelial cells), heart, ileum, and kidney. The lungs of severe COVID-19 patients demonstrate infiltration of a large number of inflammatory cells. Due to high ACE2 expression on the apical side of lung epithelial cells in the alveolar space, SARS-CoV-2 (COVID-19) can enter and destroy lung epithelial cells. Significant ACE2 expression on innate lymphoid cells (ILC)2, ILC3, and endothelial cells is also demonstrated. Pulmonary endothelial cells represent one third of the lung cells. Endothelial function includes promotion of anti-aggregation, fibrinolysis, and vasodilatation. Due to a significant role playing in thrombotic regulation, hypercoagulable profiles that are demonstrated in severe COVID-19 patients likely suggest significant endothelial injury. Pulmonary thrombosis and embolism accompanying elevation of d-dimer and fibrinogen levels have been demonstrated in severe COVID-19. In conclusion, whether these histopathological lesions are direct consequences of sepsis, SARS-CoV-2 (C)OVID-19), and /or multiple organ failure is difficult to conclude. Further studies on understanding the roles of ILC1, ILC2, ILC3, including the difference in response to SARS-CoV-2 (COVID-19) infection between children and adults are urgently needed to develop efficient targeted therapies.
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Moreno Nieves, Uriel Y., Joshua Tay, Saumyaa Saumyaa, David Mundy, and John B. Sunwoo. "Plasticity and Polarization of Human NK Cells in the Tumor Microenvironment." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 243.24. http://dx.doi.org/10.4049/jimmunol.204.supp.243.24.
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Abstract The presence and function of innate lymphoid cells (ILC), including natural killer (NK) cells, within human tumors has been poorly characterized. Here, we have assessed the heterogeneity of NK and ILC populations by single-cell RNA sequencing (scRNAseq) of hundreds of individual NK cells and ILCs within human head and neck squamous cell carcinoma (HNSCC), matched lymph node metastases, matched peripheral blood, and blood from healthy donors. Fresh tumor specimens and blood were obtained from 8 patients undergoing surgical resection of HNSCC. Unsupervised clustering revealed 8 different clusters of NK cells and ILC subsets. We observed significant heterogeneity, with distinct subsets showing profiles consistent with that of conventional NK cells, ILC1-like cells and ILC3-like cell. Importantly, peripheral NK cells were distinct from intratumoral NK cells. The presence of these different cell subsets within primary HNSCC tumors was confirmed by flow cytometry. Further, plasticity between the NK cell subsets was supported by in vitro and in vivo experimental data. Given the ability of NK and ILCs to polarize the immune responses through the secretion of cytokines and the ability of certain subsets to kill target cells, we hypothesize that the differences observed in NK and ILC populations and their plasticity may result in different immune responses, and may influence clinical outcomes following therapy.
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Hazenberg, Mette D., and Hergen Spits. "Human innate lymphoid cells." Blood 124, no. 5 (July 31, 2014): 700–709. http://dx.doi.org/10.1182/blood-2013-11-427781.
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Innate lymphoid cells (ILCs) are lymphoid cells that do not express rearranged receptors and have important effector and regulatory functions in innate immunity and tissue remodeling. ILCs are categorized into 3 groups based on their distinct patterns of cytokine production and the requirement of particular transcription factors for their development and function. Group 1 ILCs (ILC1s) produce interferon γ and depend on Tbet, group 2 ILCs (ILC2s) produce type 2 cytokines like interleukin-5 (IL-5) and IL-13 and require GATA3, and group 3 ILCs (ILC3s) include lymphoid tissue inducer cells, produce IL-17 and/or IL-22, and are dependent on RORγt. Whereas ILCs play essential roles in the innate immune system, uncontrolled activation and proliferation of ILCs can contribute to inflammatory autoimmune diseases. In this review, we provide an overview of the characteristics of ILCs in the context of health and disease. We will focus on human ILCs but refer to mouse studies if needed to clarify aspects of ILC biology.
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Gomez-Rodriguez, Julio Washington, Francoise Meylan, Robin Handon, Erika Hayes, Stacie Anderson, Martha Kirby, Richard M. Siegel, and Pamela L. Schwartzberg. "An essential role for Itk in Th9 differentiation via TCR-mediated induction of IL-2 and IRF4." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 133.35. http://dx.doi.org/10.4049/jimmunol.196.supp.133.35.
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Abstract T helper 9 (Th9) cells produce IL-9, a cytokine implicated in allergic asthma and autoimmunity. We show that Itk, a mediator of T-cell receptor signalling in Th2 immune responses and the development of asthma, is a positive regulator of Th9 differentiation in vivo and in vitro. In a papain-induced model of allergic lung disease, Itk-deficient mice have reduced pulmonary inflammation and IL-9 production by T cells and innate lymphoid type 2 cells (ILC2), despite normal induction of ILC2s. In vitro, naïve Itk−/− CD4+ T cells do not produce IL-9 and have reduced levels of IRF4, a critical transcription factor for effector T-cell function. Both IL-9 and IRF4 expression are rescued by either IL-2 or expression of constitutively-active STAT5, but not NFATc1. STAT5 binds the Irf4 promoter, indicating a mechanism by which IL-2 rescues weakly-activated T cells. Itk inhibition also reduced IL-9 expression by human CD4 T cells, thereby implicating ITK as a possible target to prevent Th9-mediated inflammatory diseases.
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Li, Jian, Andria Doty, and Sarah Glover. "Impaired AHR Signaling Contributes To Intestinal ILC3/ILC1 Conversion In The Inflamed Terminal Ileum Of Crohn’s Disease Patients." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 55.45. http://dx.doi.org/10.4049/jimmunol.198.supp.55.45.
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Abstract Introduction Crohn’s disease (CD) is one form of inflammatory bowel disease (IBD). Traditionally, adaptive immunity has been presumed to play a major role in the pathogenesis of CD. Recently, increasing evidence indicates that innate immunity also plays an essential role in this process. The phenotype and function of newly discovered innate lymphoid cells (ILCs) are crucial for the maintenance of intestinal homeostasis. Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor which is important for the regulation of ILC biology in the mouse gut. We wanted to explore the potential involvement of AHR in the regulation of intestinal ILC of CD patients. Hypothesis AHR signaling pathway is critical for the regulation of the phenotype and function of human intestinal ILC in the terminal ileum of CD patients. Methods Surgical terminal ileum samples were collected from CD patients. Histology, Real-time PCR analysis, flow cytometric analysis and immunohistochemistry staining were performed. Results The expression of AHR was correlated with CD117 expression on human intestinal ILC subsets. The IFN-γ-producing-ILC1s accumulated in the inflamed terminal ileum of CD patients at the expense of protective IL-22-producing NKp44+ILC3s. Also, the expression of both AHR and CD117 were downregulated in the ILCs from the inflamed tissue. Additionally, there was a disparity between AHR protein and mRNA expression in the inflamed gut of CD patients which suggested the involvement of a posttranscriptional mechanism. Conclusions The AHR signaling was impaired in the inflamed gut of CD patients. This transcriptional modification contributed to the ILC3/ILC1 conversion and promoted the process of intestinal inflammation.
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Li, Na, Vincent van Unen, Thomas Höllt, Allan Thompson, Jeroen van Bergen, Nicola Pezzotti, Elmar Eisemann, et al. "Mass cytometry reveals innate lymphoid cell differentiation pathways in the human fetal intestine." Journal of Experimental Medicine 215, no. 5 (March 6, 2018): 1383–96. http://dx.doi.org/10.1084/jem.20171934.
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Innate lymphoid cells (ILCs) are abundant in mucosal tissues and involved in tissue homeostasis and barrier function. Although several ILC subsets have been identified, it is unknown if additional heterogeneity exists, and their differentiation pathways remain largely unclear. We applied mass cytometry to analyze ILCs in the human fetal intestine and distinguished 34 distinct clusters through a t-SNE–based analysis. A lineage (Lin)−CD7+CD127−CD45RO+CD56+ population clustered between the CD127+ ILC and natural killer (NK) cell subsets, and expressed diverse levels of Eomes, T-bet, GATA3, and RORγt. By visualizing the dynamics of the t-SNE computation, we identified smooth phenotypic transitions from cells within the Lin−CD7+CD127−CD45RO+CD56+ cluster to both the NK cells and CD127+ ILCs, revealing potential differentiation trajectories. In functional differentiation assays, the Lin−CD7+CD127−CD45RO+CD56+CD8a− cells could develop into CD45RA+ NK cells and CD127+RORγt+ ILC3-like cells. Thus, we identified a previously unknown intermediate innate subset that can differentiate into ILC3 and NK cells.
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Puttur, Franz, Laura Denney, Lisa G. Gregory, Juho Vuononvirta, Robert Oliver, Lewis J. Entwistle, Simone A. Walker, et al. "Pulmonary environmental cues drive group 2 innate lymphoid cell dynamics in mice and humans." Science Immunology 4, no. 36 (June 7, 2019): eaav7638. http://dx.doi.org/10.1126/sciimmunol.aav7638.
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Group 2 innate lymphoid cells (ILC2s) are enriched in mucosal tissues (e.g., lung) and respond to epithelial cell–derived cytokines initiating type 2 inflammation. During inflammation, ILC2 numbers are increased in the lung. However, the mechanisms controlling ILC2 trafficking and motility within inflamed lungs remain unclear and are crucial for understanding ILC2 function in pulmonary immunity. Using several approaches, including lung intravital microscopy, we demonstrate that pulmonary ILC2s are highly dynamic, exhibit amoeboid-like movement, and aggregate in the lung peribronchial and perivascular spaces. They express distinct chemokine receptors, including CCR8, and actively home to CCL8 deposits located around the airway epithelium. Within lung tissue, ILC2s were particularly motile in extracellular matrix–enriched regions. We show that collagen-I drives ILC2 to markedly change their morphology by remodeling their actin cytoskeleton to promote environmental exploration critical for regulating eosinophilic inflammation. Our study provides previously unappreciated insights into ILC2 migratory patterns during inflammation and highlights the importance of environmental guidance cues in the lung in controlling ILC2 dynamics.
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Inaba, Akihiko, Ayane Arinaga, Keisuke Tanaka, Takaho Endo, Norihito Hayatsu, Yasushi Okazaki, Takumi Yamane, Yuichi Oishi, Hiroo Imai, and Ken Iwatsuki. "Interleukin-4 Promotes Tuft Cell Differentiation and Acetylcholine Production in Intestinal Organoids of Non-Human Primate." International Journal of Molecular Sciences 22, no. 15 (July 24, 2021): 7921. http://dx.doi.org/10.3390/ijms22157921.
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In the intestine, the innate immune system excludes harmful substances and invading microorganisms. Tuft cells are taste-like chemosensory cells found in the intestinal epithelium involved in the activation of group 2 innate lymphoid cells (ILC2). Although tuft cells in other tissues secrete the neurotransmitter acetylcholine (ACh), their function in the gut remains poorly understood. In this study, we investigated changes in the expression of genes and cell differentiation of the intestinal epithelium by stimulation with interleukin-4 (IL-4) or IL-13 in macaque intestinal organoids. Transcriptome analysis showed that tuft cell marker genes were highly expressed in the IL-4- and IL-13-treated groups compared with the control, and the gene expression of choline acetyltransferase (ChAT), a synthesis enzyme of ACh, was upregulated in IL-4- and IL-13-treated groups. ACh accumulation was observed in IL-4-induced organoids using high-performance liquid chromatography-mass spectrometry (HPLC/MS), and ACh strongly released granules from Paneth cells. This study is the first to demonstrate ACh upregulation by IL-4 induction in primates, suggesting that IL-4 plays a role in Paneth cell granule secretion via paracrine stimulation.
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Bonne-Annee, Sandra, and Thomas B. Nutman. "Modulation of human innate lymphoid cell function by IL-10." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 208.1. http://dx.doi.org/10.4049/jimmunol.198.supp.208.1.
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Abstract Although present in extremely low numbers in the human circulation at steady state, innate lymphoid cells (ILCs) are expanded in human helminth infections. Despite their low frequency (accounting for 0.21% (range 0.023–3.58%) of lymphocytes in the peripheral blood under homeostatic conditions), ILCs release extremely large quantities of cytokines following activation. If left unchecked, these cytokines can have deleterious effects on the host. We have observed that circulating ILCs demonstrate surface expression of IL-10R under homeostatic conditions. To examine how the expression of IL-10R regulates cytokine production by ILCs, ILC subsets were isolated from the peripheral blood of healthy donors by flow cytometry-based sorting and activated in the presence or absence of the immunoregulatory cytokine IL-10. ILCs stimulated in the presence of IL-10 had a marked reduction (range from 2–3.6 fold) in cytokines (IL-4, IL-5, IL-13, IL-17A, INF-γ, and TNF-α) when compared to ILCs activated without IL-10. These findings demonstrate that IL-10 signaling can inhibit cytokine production by activated ILCs. Furthermore, studies are currently underway to examine ILC subsets in the context of chronic helminth infections, where IL-10 has a modulatory effect on innate and adaptive immune cells and to identify additional mechanisms that regulate ILC cytokine production, including TGF-β.
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Spits, Hergen, Jochem Bernink, Charlotte Peters, and Jenny Mjosberg. "New Insights in Development and Function of Human Innate Lymphoid Cells." Blood 120, no. 21 (November 16, 2012): SCI—19—SCI—19. http://dx.doi.org/10.1182/blood.v120.21.sci-19.sci-19.
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Abstract Abstract SCI-19 Innate lymphoid cells (ILC) are immune cells that lack a specific antigen receptor, yet possess the capacity to produce an array of effector cytokines that in variety matches that of T-helper-cell subsets. Innate lymphoid cells function in lymphoid organogenesis, tissue remodeling antimicrobial immunity and inflammation, particularly at barrier surfaces. The ability of ILCs to promptly respond to insults inflicted by stress-causing microbes strongly suggests that ILCs are critical in first-line immunological defenses. ILCs are also involved in repair of tissue damage inflicted by pathogenic microbes. The scientific session presentation will include data on developmental requirements, lineage relationship and effector functions of human ILCs. Two families of innate lymphoid cells will be discussed: Rorγt-expressing cells involved in lymphoid tissue formation, mucosal immunity and inflammation, and Type 2 innate lymphoid cells that are important for helminth immunity. In addition, evidence will be presented for the existence of a novel ILC population that is dedicated to producing interferon-γ and which we call type 1 ILC. The potential roles of ILC in the pathology of immunity-mediated inflammatory and infectious diseases, including allergic diseases, will be discussed. Disclosures: No relevant conflicts of interest to declare.
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Ebihara, Takashi. "Dichotomous Regulation of Acquired Immunity by Innate Lymphoid Cells." Cells 9, no. 5 (May 11, 2020): 1193. http://dx.doi.org/10.3390/cells9051193.
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The concept of innate lymphoid cells (ILCs) includes both conventional natural killer (NK) cells and helper ILCs, which resemble CD8+ killer T cells and CD4+ helper T cells in acquired immunity, respectively. Conventional NK cells are migratory cytotoxic cells that find tumor cells or cells infected with microbes. Helper ILCs are localized at peripheral tissue and are responsible for innate helper-cytokine production. Helper ILCs are classified into three subpopulations: TH1-like ILC1s, TH2-like ILC2s, and TH17/TH22-like ILC3s. Because of the functional similarities between ILCs and T cells, ILCs can serve as an innate component that augments each corresponding type of acquired immunity. However, the physiological functions of ILCs are more plastic and complicated than expected and are affected by environmental cues and types of inflammation. Here, we review recent advances in understanding the interaction between ILCs and acquired immunity, including T- and B-cell responses at various conditions. Immune suppressive activities by ILCs in particular are discussed in comparison to their immune stimulatory effects to gain precise knowledge of ILC biology and the physiological relevance of ILCs in human diseases.
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Laky, Karen, Jessica L. Kinard, Anthony Guerrerio, Min Jenny Li, and Pamela Guerrerio. "Mutation of Tgfbr1 leads to non-hematopoietic defects that drive early onset eosinophilic inflammation in the esophagus." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 67.15. http://dx.doi.org/10.4049/jimmunol.202.supp.67.15.
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Abstract Eosinophilic esophagitis is a chronic disease characterized by tissue-restricted eosinophilia, epithelial basal cell hyperplasia, and esophageal dysfunction. There are three endotypes of eosinophilic esophagitis which are classified based upon the age of disease onset, degree of fibrostenosis, and gene expression patterns. Genetic studies have identified variants that correlate with an increased likelihood to develop eosinophilic esophagitis. Among the top ten variants, nearly all occur in genes expressed by epithelial cells, and approximately one-third encode proteins involved in the transforming growth factor beta (TGFβ) signaling pathway. The pathophysiologic mechanisms underlying these genetic risk factors are poorly understood. Using mice engineered to have an autosomal dominant loss-of-function mutation in the kinase domain of Tgfbr1 we demonstrate that altered TGFβ signaling in non-hematopoietic cells is necessary and sufficient to cause disease that clinically, immunologically, histologically, and transcriptionally recapitulates human eosinophilic esophagitis endotype 2. Tgfbr1 mutation impairs esophageal epithelial cell homeostasis resulting in tissue-restricted increases in proteins that act directly, indirectly, and synergistically to drive accumulation and activation of eosinophils, mast cells, and type 2 innate lymphoid cells (ILC2). These data suggest new ways to approach the prevention and treatment of eosinophilic esophagitis.
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Gao, Chunji, Xiaohong Li, Jian Ma, Xiaoxiong Wu, Feifei Wang, Meng Li, Li Yu, and Wanming Da. "Ex Vivo Expansion of Highly Purified Human NK Cells.." Blood 114, no. 22 (November 20, 2009): 2157. http://dx.doi.org/10.1182/blood.v114.22.2157.2157.
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Abstract Abstract 2157 Poster Board II-134 Object To optimize the expansion of high purity NK cells from human peripheral blood and explore the changes in biological functions of NK cells after Ex vivo expansion. Methods NK cells were isolated from PBMNC by using miniMACS (Magnetic cell-selection) and NK Cell Isolation Kit II(Miltenyi Biotec, Germany), then they were cultured in SCEM (Stemline Hematopoietic Stem Cell Expansion Medium, Sigma) supplemented with 10% human AB serum and different combinations of interleukin (IL)-2 and/or IL-12, IL-15 for 15 days. Cultures were fed with fresh media and cytokines every 3 days, and were evaluated for cell expansion, phenotype, perforin and granzyme B mRNA expressions, and IFN-γ secretion at the end of the culture period. Results In group IL2+IL15 and IL2+IL15+IL12, cells were expanded 50.46±4.31 and 52.35±6.72 fold, respectively, much more higher than others(P<0.01), but no significant difference between them (P>0.05). And the purity of CD3−CD56+NK cells was over 94% in all groups except the control. The expressions of perforin and granzyme B mRNA of expanded NK cells cultured with cytokines was significantly higher than the starting population(P<0.01), although IL2+IL15+IL12 group was slightly higher than that of IL2+IL15 group, without significant difference (P>0.05). There was great increase in IFN-γ levels in the supernatants of NK cells culture in the presence of cytokines; IL2+IL15+IL12 group and IL2+IL12 group was significantly higher than others(P<0.01). Conclusion High purity NK cells could be efficiently expanded in culture with IL2+IL15, and its biological functions were enhanced in this condition. Disclosures: No relevant conflicts of interest to declare.
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Brown, J. L., L. Campbell, J. Malcolm, A. Adrados Planell, J. P. Butcher, and S. Culshaw. "Enrichment of Innate Lymphoid Cell Populations in Gingival Tissue." Journal of Dental Research 97, no. 12 (June 21, 2018): 1399–405. http://dx.doi.org/10.1177/0022034518782141.
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Innate lymphoid cells (ILCs) are a population of lymphocytes that act as the first line of immunologic defense at mucosal surfaces. The ILC family in the skin, lungs, and gastrointestinal tissues has been investigated, and there are reports of individual subsets of ILCs in the oral tissues. We sought to investigate the whole ILC population (group 1, 2, and 3 subsets) in the murine gingivae and the lymph nodes draining the oral cavity. We show that ILCs made up a greater proportion of the whole CD45+ lymphocyte population in the murine gingivae (0.356% ± 0.039%) as compared with the proportion of ILCs in the draining lymph nodes (0.158% ± 0.005%). Cytokine profiling of the ILC populations demonstrated different proportions of ILC subsets in the murine gingivae versus the regional lymph nodes. The majority of ILCs in the draining lymph nodes expressed IL-5, whereas there were equal proportions of IFN-γ- and IL-5 expressing ILCs in the oral mucosa. The percentage of IL-17+ ILCs was comparable between the murine gingivae and the oral draining lymph nodes. These data suggest an enrichment of ILCs in the murine gingivae, and these ILCs reflect a cytokine profile discrepant to that of the local draining lymph nodes. These studies indicate diversity and enrichment of ILCs at the oral mucosal surface. The function of ILCs in the oral cavity remains to be determined; here, we provide a premise of ILC populations that merits future consideration in investigations of mouse models and human tissues.
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Rodriguez-Nieves, Jennifer, Ryan Tuck, and Kristina De Paris. "JAK/STAT Signaling of Natural Killer (NK) Cells Following Cytokine Stimulation." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 124.20. http://dx.doi.org/10.4049/jimmunol.198.supp.124.20.
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Abstract Natural Killer (NK) cells are an important component of the innate immune system, capable of providing a fast and effective response against virally infected cells. NK cells are mainly characterized by their cytotoxic function and their ability to secrete cytokines. It has been shown that infant NK cells have decreased cytotoxicity and cytokine-secreting function, suggesting hyporesponsiveness of NK cells during the first year of life. Because NK cell activation is dependent on cytokine stimulation, we hypothesized that infant NK cells are hyporesponsive due to deficiencies in signaling following cytokine stimulation. We examined the activation of human infant and adult NK cells in response to IL2, IL12 or IFNα stimulation, cytokines important in NK survival and function. Using Phosflow analysis, we measured the phosphorylation of transcription factors, STATs, specific for the distinct cytokines. Cord blood NK cells showed significantly lower pSTAT activation when compared to adult NK cells when treated with IL2 or IFNα but not IL12. However, despite pSTAT4 activation in response to IL12, no nuclear translocation was observed by ImageStreamX Mark II analysis. NK cells in 6 and 12-month-old infants showed similar frequencies of pSTAT NK cells compared to adults when treated with IL2, IL12 or IFNα, suggesting that cytokine signaling in NK cells is age-dependent. Surprisingly, pSTAT activation was restored in cord blood NK cells when treated with a cocktail of IL2, IL12 and IL15. These results suggest that JAK/STAT signaling in infant NK cells is impaired at different steps in the pathway in response to specific cytokines.
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Poniewierska-Baran, Agata, Beata Tokarz-Deptuła, and Wiesław Deptuła. "The role of innate lymphoid cells in selected disease states – cancer formation, metabolic disorder and inflammation." Archives of Medical Science 17, no. 1 (January 5, 2021): 196–206. http://dx.doi.org/10.5114/aoms.2019.89835.
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Innate lymphoid cells (ILCs) are a recently described group of immune cells that can regulate homeostasis and protect mammalian organisms, including humans, from infections and diseases. Considering this, ILC research is still ongoing to better understand the biology of these cells and their roles in the human body. ILCs are a multifunctional group of immune cells, making it important for the medical community to be familiar with the latest research about the ILC families and their functions in selected disease states, such as cancer formation, metabolic disorders and inflammation. By discovering the roles of ILC populations and their participation in many disorders, we can improve disease diagnostics and patient healthcare.
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Tait Wojno, Elia D., and David Artis. "Emerging concepts and future challenges in innate lymphoid cell biology." Journal of Experimental Medicine 213, no. 11 (October 10, 2016): 2229–48. http://dx.doi.org/10.1084/jem.20160525.
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Innate lymphoid cells (ILCs) are innate immune cells that are ubiquitously distributed in lymphoid and nonlymphoid tissues and enriched at mucosal and barrier surfaces. Three major ILC subsets are recognized in mice and humans. Each of these subsets interacts with innate and adaptive immune cells and integrates cues from the epithelium, the microbiota, and pathogens to regulate inflammation, immunity, tissue repair, and metabolic homeostasis. Although intense study has elucidated many aspects of ILC development, phenotype, and function, numerous challenges remain in the field of ILC biology. In particular, recent work has highlighted key new questions regarding how these cells communicate with their environment and other cell types during health and disease. This review summarizes new findings in this rapidly developing field that showcase the critical role ILCs play in directing immune responses through their ability to interact with a variety of hematopoietic and nonhematopoietic cells. In addition, we define remaining challenges and emerging questions facing the field. Finally, this review discusses the potential application of basic studies of ILC biology to the development of new treatments for human patients with inflammatory and infectious diseases in which ILCs play a role.
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Teunissen, M. B., L. B. Møller, MB Løvendorf, C. M. Bonefeld, L. Skov, M. Mann, and B. Dyring Andersen. "195 Proteomic Analyses of ILC2 and ILC3 from Human Skin and Peripheral Blood Reveal Distinctive Phenotypes and Functions." Journal of Investigative Dermatology 141, no. 10 (October 2021): S182. http://dx.doi.org/10.1016/j.jid.2021.08.200.
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Ahn, Yong-Oon, Bruce R. Blazar, Jeffrey S. Miller, and Michael R. Verneris. "Human IL-22 Producing CD56+ RORγt+ Innate Lymphoid Cells and Conventional NK Cells Have Distinctive Developmental Trajectories and Are Separate Cell Lineages." Blood 120, no. 21 (November 16, 2012): 1219. http://dx.doi.org/10.1182/blood.v120.21.1219.1219.
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Abstract Abstract 1219 Human IL-22 producing RORγt+ innate lymphoid cells (ILC22) and conventional NK (cNK) cells are present in secondary lymphoid tissues. Both cell types have an immunophenotype that correspond to stage III NK progenitors (CD56+/−CD117highCD94−), leading us and others to speculate that the IL-22 producing cells are part of the NK lineage and can give rise to cNK cells (Tang, Blood, 2010, Cupedo, Nat Imm, 2009 and Colona, Immunity, 2009). However, recent fate mapping studies in mice suggest that these cell types are separate lineages (Sawa, Science 2010). Given the significant phenotypic and functional differences between human and murine ILC22 cells, this issue is unresolved in humans. To address this, we used an established differentiation system where UCB-derived CD34+ cells are cultured on irradiated fetal liver stromal cells in the presence of IL-3 (5 ng/ml, for the first week), IL-7 (20 ng/ml), SCF (20 ng/ml), FLT3L (10 ng/ml) and IL-15 (10 ng/ml). We have previously demonstrated that this model precisely recapitulates NK cell developmental intermediates, as well as IL-22 producing ILCs (Gryzwacz, Blood, 2005 and Tang, Blood, 2011). We first set out to determine whether it was possible to distinguish IL-22 producing ILCs from cNK using intracellular cytokine staining and a panel of mAbs. Non-IL-22 producing cNK cells showed a CD56+CD117lo/-CD7+/−LFA-1high phenotype, while ILC22 cells were completely contained within the CD56+CD117highCD94−CD7−LFA-1− fraction. Purification of these two populations showed that ILC22 cells expressed high quantities of transcription factors associated with IL-22 production including AhR and RORγt, while these were absent or barely detectable in cNK cells (p<0.0001). Conversely, T-bet and Eomes were highly expressed in cNK progenitors, but not ILC22 cells. While cNK cells expressed granzyme and perforin, classical NK-associated receptors (NKp30, NKp46, NKG2A, NKG2D, CD8, CD16 and KIR) and showed degranulation (CD107a) and produced IFN-γ in response to K562 targets or IL-12+IL-18, ILC22 cells did not. Thus, ILC22 and cNK cells were distinguishable by transcription factor expression, surface receptor expression and function. To investigate the lineage relationship between ILC22 cells and cNK cells, stage III NK progenitors (defined as CD56+CD117+CD94−) were purified on the basis of LFA-1 expression and then further cultured. Cells that expressed LFA-1 (i.e., cNK progenitor cells) rapidly acquired CD94, and differentiated into stage IV and V cNK cells. Conversely, the vast majority of cells that lacked LFA-1 cells (i.e., ILC22 cells) acquired neither LFA-1 nor CD94, thus never differentiate into stage IV and V cNK cells. These results suggest that ILC22 cells represent a separated and stable cell lineage from cNK cells. To further address this and investigate the developmental requirements for cNK and ILC22 cells, CD34+ hematopoietic stem cells were cultured in the above conditions with or without IL-7 and SCF, which are known to be critical cytokines for lymphoid tissue inducer (LTi) cell generation in vivo (a population similar to ILC22 cells). In the absence of IL-7 and SCF, cNK cells developed normally while ILC22 cells did not develop. These results show that cNK cells differentiated even in the absence of ILC22 stage III cells, which require SCF and IL-7 for differentiation. Conversely, in the absence of IL-15, CD34+ cells showed a complete block in cNK differentiation and instead gave rise to a CD56+ILC22 cells, and their phenotype and function were normal. Thus, while human ILC22 cells and cNK progenitors have a phenotype that overlaps with stage III NK progenitors, these studies demonstrate that they are separate cell lineages, with differing phenotype, transcription factor expression, developmental requirements and functions. Disclosures: Miller: Celgene: Membership on an entity's Board of Directors or advisory committees; Coronado Bioscience: Membership on an entity's Board of Directors or advisory committees.
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Maggi, Laura, Manuela Capone, Alessio Mazzoni, Francesco Liotta, Lorenzo Cosmi, and Francesco Annunziato. "Plasticity and regulatory mechanisms of human ILC2 functions." Immunology Letters 227 (November 2020): 109–16. http://dx.doi.org/10.1016/j.imlet.2020.08.004.
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Zhu, Xiaoliang, and Jinfang Zhu. "CD4 T Helper Cell Subsets and Related Human Immunological Disorders." International Journal of Molecular Sciences 21, no. 21 (October 28, 2020): 8011. http://dx.doi.org/10.3390/ijms21218011.
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The immune system plays a critical role in protecting hosts from the invasion of organisms. CD4 T cells, as a key component of the immune system, are central in orchestrating adaptive immune responses. After decades of investigation, five major CD4 T helper cell (Th) subsets have been identified: Th1, Th2, Th17, Treg (T regulatory), and Tfh (follicular T helper) cells. Th1 cells, defined by the expression of lineage cytokine interferon (IFN)-γ and the master transcription factor T-bet, participate in type 1 immune responses to intracellular pathogens such as mycobacterial species and viruses; Th2 cells, defined by the expression of lineage cytokines interleukin (IL)-4/IL-5/IL-13 and the master transcription factor GAΤA3, participate in type 2 immune responses to larger extracellular pathogens such as helminths; Th17 cells, defined by the expression of lineage cytokines IL-17/IL-22 and the master transcription factor RORγt, participate in type 3 immune responses to extracellular pathogens including some bacteria and fungi; Tfh cells, by producing IL-21 and expressing Bcl6, help B cells produce corresponding antibodies; whereas Foxp3-expressing Treg cells, unlike Th1/Th2/Th17/Tfh exerting their effector functions, regulate immune responses to maintain immune cell homeostasis and prevent immunopathology. Interestingly, innate lymphoid cells (ILCs) have been found to mimic the functions of three major effector CD4 T helper subsets (Th1, Th2, and Th17) and thus can also be divided into three major subsets: ILC1s, ILC2s, and ILC3s. In this review, we will discuss the differentiation and functions of each CD4 T helper cell subset in the context of ILCs and human diseases associated with the dysregulation of these lymphocyte subsets particularly caused by monogenic mutations.
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Wiarda, Jayne E., Julian M. Trachsel, Sathesh K. Sivasankaran, Christopher K. Tuggle, and Crystal L. Loving. "Gene signatures for intestinal and peripheral innate lymphoid cells in pigs reveal tissue-specific imprinting and similarities to human cells via single-cell RNA sequencing." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 171.11. http://dx.doi.org/10.4049/jimmunol.208.supp.171.11.
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Abstract Intestinal innate lymphoid cells (iILCs) impact intestinal health outcomes, but study of iILCs in humans is limited. Human peripheral ILCs (pILCs) are easily obtained but may vary substantially from iILCs, thus requiring comparison of iILCs and pILCs to determine applicability of pILCs as surrogates to study iILC function. Pigs have anatomic, physiological, nutritional, and immune similarities to humans that are lacking in rodent models, making pigs a relevant biomedical model; however, ILCs are poorly defined in pigs. Single-cell RNA sequencing was performed to compare porcine iILCs to pILCs and determine potential similarities of porcine to human ILCs. Porcine pILCs matched porcine natural killer (NK) cell descriptions, while iILCs were annotated as group 1 and group 3 ILCs. Gene modules obtained independent of cell annotations were distilled to core signatures of genes most highly specific to pILCs, pan-iILCs, group 1 iILCs, and group 3 iILCs. The pILC signature included conventional NK cell genes, while the group 3 iILC signature included genes associated with type 3 immunity. Pan-iILC and group 1 iILC signatures included genes associated with tissue residency, cell activation, and metabolism, indicating tissue-specific, activation-associated imprinting. Gene profiles were used to develop in situ iILC detection methods, establishing group 1 iILCs were intraepithelial, while group 3 iILCs resided in lamina propria/gut-associated lymphoid tissue. Findings indicated iILCs were ILC subsets distinct from pILCs, thus opposing pILCs as surrogates to study iILC dynamics. Moreover, gene profiles and in situ locations of iILCs drew close parallels to human iILCs functions, supporting pigs as a biomedical model for iILC research. Research was supported by appropriated funds from USDA-ARS CRIS 5030-31320-004-00D, an appointment to the Agricultural Research Service (ARS) Research Participation Program administered by the Oak Ridge Institute for Science and Education (ORISE) through an interagency agreement between the U.S. Department of Energy (DOE) and the U.S. Department of Agriculture (USDA). ORISE is managed by ORAU under DOE contract number DE-SC0014664. All opinions expressed in this paper are the authors’ and do not necessarily reflect the policies and views of USDA, ARS, DOE, or ORAU/ORISE. This research used resources provided by the SCINet project of the USDA ARS project number 0500-00093-001-00-D.
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Rabinowich, Hannah, Ronald B. Herberman, and Theresa L. Whiteside. "Differential Effects of IL12 and IL2 on Expression and Function of Cellular Adhesion Molecules on Purified Human Natural Killer Cells." Cellular Immunology 152, no. 2 (December 1993): 481–98. http://dx.doi.org/10.1006/cimm.1993.1306.
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Colmenares, V., D. E. Noyola, A. Monsiváis-Urenda, M. Salgado-Bustamante, L. Estrada-Capetillo, R. González-Amaro, and L. Baranda. "Human Papillomavirus Immunization Is Associated with Increased Expression of Different Innate Immune Regulatory Receptors." Clinical and Vaccine Immunology 19, no. 7 (May 9, 2012): 1005–11. http://dx.doi.org/10.1128/cvi.00043-12.
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ABSTRACTHuman papillomavirus (HPV) is able to inhibit the secretion of gamma interferon (IFN-γ) and the expression of some immune innate cell receptors. Immunoglobulin-like transcript 2 (ILT2) is a regulatory receptor that seems to participate in the pathogenesis of viral infections. We have studied the expression and function of ILT2 and the expression of other NK cell receptors in 23 healthy women before and after immunization with the quadrivalent HPV (type 6/11/16/18) vaccine (Gardasil). Receptor expression was analyzed by flow cytometry in freshly isolated peripheral blood mononuclear cells as well as afterin vitrostimulation with the quadrivalent HPV (type 6/11/16/18) vaccine. In addition, the regulatory function of ILT2 on cell proliferation and IFN-γ production was analyzed. We found a significant increase in the expression of ILT2 by NK and CD3+CD56+lymphocytes and monocytes after quadrivalent HPV (type 6/11/16/18) vaccine immunization. In addition, thein vitrostimulation with the quadrivalent HPV (type 6/11/16/18) vaccine also increased the proportion of CD3−CD56+ILT2+NK cells. Although the inhibitory function of ILT2 on cell proliferation was enhanced after HPV immunization, thein vitroengagement of this receptor did not affect the synthesis of IFN-γ induced by HPV. Finally, a significant increase in the expression of NKG2D, NKp30, and NKp46 by NK and CD3+CD56+lymphocytes was detected after quadrivalent HPV (type 6/11/16/18) vaccine immunization. Our data indicate that HPV immunization is associated with significant changes in the expression and function of different innate immune receptors, including ILT2, which may participate in the protective effect of HPV vaccines.
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Sartor, Mary M., Jenny Lau, David Gottlieb, and Kenneth F. Bradstock. "Increased Production of the Inflammatory Cytokine IL12p70 by Activated Human Blood Dendritic Cells Is Associated with Increased Severity of Acute Graft Vs Host Disease Post Allogeneic Hemopoietic Cell Transplantation." Blood 118, no. 21 (November 18, 2011): 4539. http://dx.doi.org/10.1182/blood.v118.21.4539.4539.
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Abstract Abstract 4539 Introduction: Dendritic cells (DC) are centrally involved in the initiation of acute graft versus host disease (GVHD) after allogeneic hemopoietic cell transplantation (alloHCT). We have shown that the activation status of peripheral blood CD11c+ myeloid DC, as assessed by CMRF-44 antigen expression, is highly associated with the occurrence and severity of acute GvHD (Transplantation 2007;83: 839–846). However, very little is known about the function of DC after human alloHCT. We examined the relationship between DC functional properties and the severity of acute GvHD. Methods: Peripheral blood CD11c+ myeloid DC from 12 patients were studied weekly up to 8 weeks post transplant for production of IL2, IL4, INFg, IL10 and IL12 using an intracellular cytokine flow assay. Mixed lymphocyte reactions using flow sorted patient DC and third party T cells were used to assess allogeneic immune responses induced by recipient DC in 5 patients. Results: IL12 was the only cytokine detected in post transplant DC. Five of 12 patients developed grade II-IV GvHD, the remaining 7 patients developed either no aGvHD or only grade I. In comparison with pre-transplant levels of expression of IL12, patients with grade II-IV GVHD had a significantly higher percentage of CD11c+ DC expressing IL12 (median 15.1%, range 11.2–20.9%) as compared to patients with grade 0-I GvHD in whom there was no change from baseline values (median 6.6% range 2.8–8.9%) p=0.0025. Increased expression of IL12 was observed in CD11c+ DC commencing at day 25 post transplant. Interestingly, analysis of 5 paired samples comparing sorted DC from normal donors with sorted DC from peripheral blood at day +30 post-transplant showed a marked reduction (measured by thymidine uptake from 60% to 90%) in the capacity of post-transplant donor DCs to stimulate 3rd party lymphocyte proliferation. None of these patients developed clinically significant aGvHD. Conclusion: Production of IL-12p70 by CD11c+ myeloid DC correlates with severity of GvHD despite impaired capacity of these cells to elicit third party proliferative responses. Disclosures: No relevant conflicts of interest to declare.
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Collins, Patrick, Marina Cella, Sofia Porter, Matthew Mccullen, Marco Colonna, and Eugene M. Oltz. "Regulatory circuits governing identity and function of human type 1 ILCs." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 170.20. http://dx.doi.org/10.4049/jimmunol.200.supp.170.20.
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Abstract Innate lymphocytes develop from common progenitors but diverge functionally into a broad range of subsets that comprise a rapid response system to pathogens. In mice, type 1 innate lymphoid cells (ILCs), characterized by IFN-g expression, segregate into two major groups: cytotoxic natural killer (NK) cells and cytokine-producing, helper like ILC1s. In humans, this functional dichotomy is complicated further by heterogenous populations of circulating or tissue-resident NK cells, which exhibit distinct potentials for cytotoxicity or cytokine expression. Although developmental and functional kinships among NK cells have been studied extensively in mice, little is known about the molecular programs governing NK populations in humans. Here, we present integrated “-omics” analysis of human type 1 ILCs from blood and mucosal tissues, which identifies the key factors and biologic pathways establishing cell-type and functional identifies, as well as their underlying gene regulatory programs.
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Knipfer, Lisa, Anja Schulz-Kuhnt, Markus Kindermann, Vicky Greif, Cornelia Symowski, David Voehringer, Markus F. Neurath, Imke Atreya, and Stefan Wirtz. "A CCL1/CCR8-dependent feed-forward mechanism drives ILC2 functions in type 2–mediated inflammation." Journal of Experimental Medicine 216, no. 12 (September 19, 2019): 2763–77. http://dx.doi.org/10.1084/jem.20182111.
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Group 2 innate lymphoid cells (ILC2s) possess indispensable roles during type 2–mediated inflammatory diseases. Although their physiological and detrimental immune functions seem to depend on the anatomical compartment they reside, their tissue tropism and the molecular and immunological processes regulating the self-renewal of the local pool of ILC2s in the context of inflammation or infection are incompletely understood. Here, we analyzed the role of the CC-chemokine receptor CCR8 for the biological functions of ILC2s. In vitro and in vivo experiments indicated that CCR8 is in comparison to the related molecule CCR4 less important for migration of these cells. However, we found that activated mouse and human ILC2s produce the CCR8 ligand CCL1 and are a major source of CCL1 in vivo. CCL1 signaling to ILC2s regulates their proliferation and supports their capacity to protect against helminthic infections. In summary, we identify a novel chemokine receptor–dependent mechanism by which ILC2s are regulated during type 2 responses.
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Youssef, Youssef, Ansel P. Nalin, Jesse Kowalski, Megan Broughton, Matthew Lordo, Adam Gerhardt, Ekaterina Altynova, et al. "CD200R1 Distinguishes Uncommitted Precursors from Functionally Mature NK Cells within the Human Tonsil Stage 4A NK Cell Population." Blood 138, Supplement 1 (November 5, 2021): 993. http://dx.doi.org/10.1182/blood-2021-151783.
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Abstract Natural killer (NK) cells are cytotoxic innate lymphoid cells (ILCs) whose development and anti-tumor functions can be critical for the successful treatment and long-term disease-free survival of patients with hematologic malignancies. In humans, NK cells derive from bone marrow resident hematopoietic progenitor cells that traffic to secondary lymphoid tissues (SLTs) where they complete their terminal differentiation and maturation through a series of developmental stages before returning to the blood as mature NK cells. Although major stages of human NK cell development in SLTs have been clearly defined according to the differential surface expression of CD34, CD117, CD94, NKp80, CD16, and CD57 among lineage antigen (Lin) negative lymphocytes, continued investigation has revealed additional phenotypic and functional heterogeneity at each developmental stage. Through extensive ex vivo single-cell RNA sequencing and flow cytometry analyses we have identified two subsets of tonsil-resident Lin -CD34 -CD117 +/-CD94 +NKp80 -CD16 -CD57 - stage 4A NK cells. These two subsets differ in their expression of the inhibitory receptor, CD200R1, which is not expressed by mature NK cells in the peripheral blood from healthy individuals. The majority of stage 4A cells expressed high amounts of surface CD200R1, which correlated with low gene and undetectable protein expression of intracellular cytolytic granules (perforin and granzymes A, B, K, and M), killer immunoglobulin-like receptors (KIRs), and transcription factors required for terminal NK cell maturation (EOMES, T-BET). In addition, upon ex vivo stimulation with phorbol 12-myristate 13-acetate (PMA) and ionomycin, CD200R1 + stage 4A NKDIs did not produce interferon-gamma (IFN-g), a hallmark feature of mature NK cells. In contrast, many CD200R1 - stage 4A cells constitutively expressed perforin, granzymes, EOMES, and/or T-BET; many expressed KIRs; and many produced IFN-g upon ex vivo stimulation. Furthermore, the frequency of KIR + cells among CD200R1 - stage 4A cells was significantly higher than that among autologous tonsil stage 4B NK cells (Lin -CD34 -CD117 +/-CD94 +NKp80 +CD16 -CD57 -) (20.8 ± 1.65 vs. 8.12 ± 1.66; p < 0.01; n = 14), suggesting that as a population CD200R1 - stage 4A cells are potentially out of sequence in terms of the linear NK cell developmental pathway. Based on these ex vivo findings, we hypothesized that CD200R1 + stage 4A cells represent NK cell precursors, whereas the CD200R1 - stage 4A population contains more mature NK cells that lack NKp80, CD16, and CD57. To further address this hypothesis and to determine their ex vivo potentials for NK cell and non-NK ILC differentiation, we cultured CD200R1 + and CD200R1 - stage 4A cells in vitro in the presence of OP9-DL1 stroma and recombinant human IL-7 and IL-15, conditions previously shown to support all human ILC and NK cell subset differentiation. Under these conditions, both stage 4A populations generated NKp80 + NK cells in bulk and single-cell clonal assays, whereas neither population gave rise to ILC2s (CD294 +) which precede stage 4A NK cells in the developmental scheme. However, while the majority of cultures derived from CD200R1 + stage 4A clones contained ILC3s (CD94 -NKp44 +), significantly fewer clones from CD200R1 - stage 4A cells produced ILC3s (7 of 26 CD200R1 - clones vs. 20 of 23 CD200R1 + clones; p = 0.000587). Moreover, none of the CD200R1 - stage 4A-derived clonal cultures that contained KIR + NK cells contained ILC3s, suggesting that the majority of CD200R1 - stage 4A cells are lineage committed NK cells. Collectively, these data further characterize the heterogeneity of the human tonsil stage 4A NK cell population and identify CD200R1 as a marker distinguishing uncommitted precursor cells from a minor population of cells with otherwise mature NK-associated phenotype and function. In light of the role of CD200R1 in regulating lymphocyte functions in the setting of cancer, further research is warranted to determine its potential role(s) in regulating human NK cell development. Disclosures Blachly: KITE: Consultancy, Honoraria; INNATE: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria.
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Shin, June, Nina Horowitz, Quan Tran, Chen Chen, Uriel Moreno-Nieves, Joshua Tay, Saumyaa Saumyaa, and John Sunwoo. "215 Tissue-resident natural killer cells resembling intraepithelial ILC1 have potent anti-tumor activity in human head and neck cancer and represent a novel class of effector cells for immunotherapy." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A228. http://dx.doi.org/10.1136/jitc-2021-sitc2021.215.
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BackgroundNatural killer (NK) cells comprise a subset of the innate lymphoid cell (ILC) family. Although NK cells have been observed to be present in most solid tumors, their role in the protection against tumor formation in humans has been unclear. Studies have been hampered by the heterogeneity of NK cells within the tumor microenvironment (TME) and lack of information about the broader ILC subsets found in tumors. Further, there is an increasing recognition of plasticity between NK cells and other ILC family members in various disease contexts, calling for a broader examination of ILCs within solid tumors. We previously analyzed the ILC population in primary samples from human head and neck squamous cell carcinoma (HNSCC) and matched blood by single-cell RNA sequencing (scRNA-seq).1 Those studies revealed that peripheral NK cells differentiate along two divergent trajectories in the TME, resulting in different end-states: one with a hyporesponsive phenotype and another possessing potent anti-tumor activity and resembling intraepithelial ILC1s (ieILC1s).MethodsIn vitro co-culture approaches and in vivo mouse models were used to investigate the ability of peripheral NK cells to differentiate into alternate ILC states with heterogeneous functions. Cytotoxicity assays were used to assess functional activity of in vitro derived ieILC1-like cells. Adoptive cell transfer of ieILC1-like cells into tumor-bearing mice was also used to assess anti-tumor function.ResultsPeripheral human NK cells could be efficiently differentiated into ieILC1-like cells using an in vitro co-culture system. These ieILC1-like cells had enhanced natural cytotoxicity against target cells compared to conventional IL-15-activated and K562-expanded NK cells. In addition, they infiltrated the TME efficiently and were a more effective means of adoptive cell therapy against HNSCC solid tumor xenografts in vivo compared to conventional NK cells.ConclusionsOur data indicate that peripheral NK cells change cell states within the TME of HNSCC. The heterogeneity in the relative proportion of the cell states may influence host response to tumors. We identified the ieILC1-like cell state to be the phenotype with the most potent anti-tumor activity within the TME. Importantly, this cell state can be induced from peripheral donor NK cells ex vivo for differentiation into and expansion of highly active ieILC1-like cells, providing a platform for a novel class of effector cells for adoptive cell immunotherapy.AcknowledgementsThese studies were supported by the Lokey Stem Cell Research Building (SIM1) Flow Cytometry core facility for cell sorting and flow cytometric analysis and the Stanford Cancer Institute Tissue Bank for procurement of tumor samples and blood. This work was supported by funding from the National Institutes of Health (R01CA158516; R35DE030054; U54CA209971) to J.B.S.ReferenceMoreno-Nieves UY, Tay JK, Saumyaa S, Shin JH, Horowitz NB, Mohammad IA, Luca B, Mundy DC, Gulati GS, Bedi N, Chang S, Chen C, Kaplan MJ, Rosenthal EL, Holsinger FC, Divi V, Baik FM, Sirjani DB, Gentles AJ, Newman AM, Freud AG, Sunwoo JB. Landscape of ILCs in human head and neck cancer reveals divergent NK cell states in the tumor microenvironment. Proc Natl Acad Sci U S A 2021;118(28):e2101169118.Ethics ApprovalThe studies reported here were approved by the Stanford Institutional Review Board (IRB 11402) and the Stanford Administrative Panel on Laboratory Animal Care (APLAC 20547).