Type I interferon limits ILC2 effector functions through suppression of the CCR8-CCL1/CCL8 axis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA746475 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15130670_1.fastq.gz | Fastqsanger.gz | |||
| SRR15130670_2.fastq.gz | Fastqsanger.gz | |||
| SRR15130671_1.fastq.gz | Fastqsanger.gz | |||
| SRR15130671_2.fastq.gz | Fastqsanger.gz | |||
| SRR15130672_1.fastq.gz | Fastqsanger.gz |
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Project description:Group 2 innate lymphoid cells (ILC2s) exert critical roles in anti-helminth immunity and the pathogenesis of allergic diseases by rapidly secreting vast amounts of type 2 signature cytokines. Type 1 interferons (IFN-I) are critical negative regulators of ILC2 effector functions and associated innate and adaptive type 2 immunopathologies. Exposure to IFN-I inhibits ILC2 proliferation as well as type 2 cytokine production, however, the mechanistic underpinnings of IFN-I-mediated ILC2 regulation remain largely elusive. Using RNA-sequencing analysis, we demonstrate that IFN-I treatment inhibits the production of the chemokine CCL1 by ILC2s. Moreover, expression of CCR8, the cognate chemokine receptor for CCL1, is downregulated upon IFN-I-stimulation ex vivo as well as in vivo upon sublethal influenza A virus infection (IAV) or upon IFN-I administration following pulmonary IL-33 challenge. In addition, expression of CCL8, the chemotactic ligand of CCR8, was suppressed in an IFN-I dependent manner in the lungs of IAV-infected mice. IFN-b potently restrained pulmonary CCL1/CCL8 expression as well as CCR8 expression by ILC2 and CD4+ T cells in a model of IL-33-driven allergic airway inflammation. Thus, this study sheds new light on the underlying mechanisms of ILC2 regulation by identifying the CCR8-CCL1/CCL8 axis as a target for IFN-I-driven ILC2 inhibition.
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Project description:Tumours progress despite being infiltrated by effector T cells. Tumour necrosis is associated with poor survival in a variety of cancers. Here, we report that that necrosis causes release of an intracellular ion, potassium, into the extracellular fluid of human and mouse tumours. Surprisingly, elevated extracellular potassium ([K+]e) was sufficient to profoundly suppress mouse and human T cell anti-tumour function. Elevations in [K+]e acted to acutely impair T cell receptor (TCR) dependent Akt-mTOR phosphorylation and effector function. Potassium mediated suppression of Akt-mTOR signalling and T cell effector function required intact activity of PP2A, a serine/threonine phosphatase. The suppressive effect mediated by elevated [K+]e required a T cell-intrinsic increase in intracellular potassium ([K+]i) and was independent of changes in plasma membrane potential (Vm). Finally, ionic reprogramming of tumour-specific T cells via over-expression of the voltage-gated potassium channel Kv1.3 lowered [K+]i and improved effector functions in vitro and in vivo, with this gain of function being dependent on intact channel function. Consequently, Kv1.3 T cell expression enhanced tumour clearance and the survival of melanoma-bearing mice. These results uncover a previously undescribed ionic checkpoint against T cell function within tumours and identify new strategies for cancer immunotherapy. RNA expression was measured by RNA-Seq on day 5 of cultures, maintained in individual biologial triplicates which were stimulated with immobilized anti-CD3/28 antibodies or kept in complete media (no stim) - with equivalent conditions treated with isotonic media containing elevated potassium.
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Project description:Neuropeptide CGRP limits ILC2 responses and constrains type 2 inflammation
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Project description:Group 2 innate lymphoid cells (ILC2s) rapidly induce a type 2 inflammation in the lungs in response to allergens. Here, we focused on the role of iron – a critical nutritional trace element – on ILC2 function and asthma pathogenesis. In the lungs, transferrin receptor 1 (TfR1) is rapidly upregulated and functional during ILC2 activation, while blocking transferrin uptake reduces ILC2 expansion and activation. Iron deprivation reprograms ILC2 metabolism, inducing a HIF-1a-driven upregulation of glycolysis and inhibition of oxidative mitochondrial activity. Consequently, in vivo iron chelation or induction of hypoferremia notably reduces the development of airway hyperreactivity in experimental models of ILC2-driven allergic asthma. Human circulating ILC2s rapidly induce TfR1 during activation, while iron deprivation reduces effector functions. Finally, we found a negative relation between circulating ILC2 TfR1 expression and airway function in cohorts of patients with asthma. Collectively, our studies define cellular iron as a critical regulator of ILC2 function.
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Project description:Type-2 innate lymphoid cells (ILC2) are part of a growing family of innate lymphocytes known for their crucial role in both the development and exacerbation of allergic asthma. In this study, we aim to elucidate the critical role of the suppressor molecule signal regulatory protein alpha (SIRPα), which interacts with CD47, in controlling ILC2-mediated airway hyperreactivity (AHR). Our data indicate that activated ILC2s upregulate the expression of SIRPα, and the interaction between SIRPα and CD47 effectively suppresses both ILC2 proliferation and effector function. To evaluate the efficacy of SIRPα in regulating ILC2-mediated AHR, we utilized SIRPα and CD47 deficient mice in a murine model of allergen-induced AHR. Our findings suggest that the absence of SIRPα leads to the overactivation of ILC2s. Conversely, engagement with SIRPα reduces ILC2 cytokine production and effectively regulates ILC2-dependent AHR. Furthermore, the SIRPα-CD47 axis modulates mitochondrial metabolism through the JAK/STAT and ERK/MAPK signaling pathways, thereby regulating NF-κB activity and the production of type two cytokines. Additionally, our studies on human cells have revealed that SIRPα is inducible and expressed on human ILC2s, and administration of a SIRPα agonist effectively suppresses the effector function and cytokine production of ILC2s. Moreover, administering human CD47-Fc to humanized ILC2 mice effectively alleviated AHR and lung inflammation. These findings highlight the promising therapeutic potential of targeting the SIRPα-CD47 axis in the treatment of ILC2-dependent allergic asthma.
2024-08-10 | GSE264061 | GEO
Project description:Group 2 innate lymphoid cells (ILC2) are functionally poised, tissue-resident lymphocytes that respond rapidly to damage and infection at mucosal barrier sites. ILC2 reside within complex microenvironments where they are subject to cues from both the diet and invading pathogens – including helminths. Emerging evidence suggests ILC2 are acutely sensitive not only to canonical activating signals, but also perturbations in nutrient availability. In the context of helminth infection, we identify amino acid availability as a nutritional cue in regulating ILC2 responses. ILC2 were found to be uniquely pre-primed to import amino acids via the large neutral amino acid transporters Slc7a5 and Slc7a8. Cell-intrinsic deletion of these transporters individually impaired ILC2 expansion, while concurrent loss of both transporters markedly impaired the proliferative and cytokine producing capacity of ILC2. Moreover, amino acid determined the magnitude of ILC2 responses in part via tuning of mTOR. These findings implicate essential amino acids as a metabolic requisite for optimal ILC2 responses within mucosal barrier tissues.
2022-12-22 | PXD038792 | Pride
Project description:Tumours progress despite being infiltrated by effector T cells. Tumour necrosis is associated with poor survival in a variety of cancers. Here, we report that that necrosis causes release of an intracellular ion, potassium, into the extracellular fluid of human and mouse tumours. Surprisingly, elevated extracellular potassium ([K+]e) was sufficient to profoundly suppress mouse and human T cell anti-tumour function. Elevations in [K+]e acted to acutely impair T cell receptor (TCR) dependent Akt-mTOR phosphorylation and effector function. Potassium mediated suppression of Akt-mTOR signalling and T cell effector function required intact activity of PP2A, a serine/threonine phosphatase. The suppressive effect mediated by elevated [K+]e required a T cell-intrinsic increase in intracellular potassium ([K+]i) and was independent of changes in plasma membrane potential (Vm). Finally, ionic reprogramming of tumour-specific T cells via over-expression of the voltage-gated potassium channel Kv1.3 lowered [K+]i and improved effector functions in vitro and in vivo, with this gain of function being dependent on intact channel function. Consequently, Kv1.3 T cell expression enhanced tumour clearance and the survival of melanoma-bearing mice. These results uncover a previously undescribed ionic checkpoint against T cell function within tumours and identify new strategies for cancer immunotherapy.
2016-08-13 | GSE84996 | GEO
Project description:Blocking CD226 regulates ILC2 effector function and alleviates airway hyperreactivity
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Project description:Type 2 innate lymphoid cells (ILC2s) play a pivotal role in type 2 asthma. CD226 is a costimulatory molecule involved in various inflammatory diseases. Here, we aimed to investigate CD226 expression and function within human and mouse ILC2s, and to assess the impact of targeting CD226 on ILC2-mediated airway hyperreactivity (AHR). Our findings demonstrated an inducible expression of CD226 in activated ILC2s, enhancing their cytokine secretion and effector functions. Blocking CD226 ameliorates ILC2-dependent AHR in IL-33 and Alternaria Alternata-induced models. Interestingly, CD226 is expressed and inducible in human ILC2s, and its blocking reduces cytokine production. Finally, we showed that peripheral ILC2s in asthmatic patients exhibited elevated CD226 expression compared to healthy controls.Our findings underscore the potential of CD226 as a novel therapeutic target in ILC2s, presenting a promising avenue for ameliorating AHR and allergic asthma.
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Project description: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. Compared to females, males harbor significantly fewer lung ILC2s, which express notably high levels of androgen receptor (AR) compared to other lymphocytes. Here we tested the hypothesis that females and males show differential ILC2 responses upon influenza virus (IAV) infection of mice. Over the course of sublethal 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 propensity to produce IL-5 and amphiregulin, and reduced expression of GATA3 and IL-33R. Naïve female ILC2s showed higher expression of IFNGR and higher phospho-STAT1 levels following stimulation by IFN, and lymphocyte-restricted STAT1 deficiency reversed suppression of female ILC2s during infection. 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 or lymphocyte-restricted loss of AR revealed that endogenous androgens decreased ILC2 numbers but protected males from suppression of ILC2s in IAV infection. In sum, intrinsic AR activity preserves canonical ILC2 function in males during IAV infection, which may contribute to the sex differences in morbidity secondary to IAV observed in mice and humans.
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