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Article
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Pretreatment with IL-15 and IL-18 rescues natural killer cells from granzyme B-mediated apoptosis after cryopreservation
Natural killer (NK) cells are assessed for various therapies, but sub-optimal cryopreservation dampens their clinical feasibility. Here the authors show that pretreating human NK cells with IL-15/IL-18 prior to cryopreservation improves NK cell post-thaw viability and functions, potentially via anti-apoptosis gene induction and granzyme B degranulation.
- Abdulla Berjis
- , Deeksha Muthumani
- & Neil C. Sheppard
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Article
| Open Access
Dysregulation of Wnt/β-catenin signaling contributes to intestinal inflammation through regulation of group 3 innate lymphoid cells
RORγt+ group 3 innate lymphoid cells are intimately involved in intestinal homeostasis, their dysregulation is linked to inflammatory gut diseases. Here the authors show that dysregulated Wnt/β-catenin signalling contributes to disturbed regulation of group 3 innate cells and intestinal inflammation.
- Jiacheng Hao
- , Chang Liu
- & Xiaohuan Guo
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Article
| Open Access
BET inhibitors drive Natural Killer activation in non-small cell lung cancer via BRD4 and SMAD3
Combination of BET inhibitors (BETi) with immunotherapy has been reported to be synergic for the treatment of non-small cell lung carcinoma (NSCLC). Here, the authors show that BETi-induced epigenetic reprogramming downregulates the expression of NK cell inhibitory receptors on NK cells, increasing their activation and cytotoxicity against NSCLC.
- Francesca Reggiani
- , Giovanna Talarico
- & Valentina Sancisi
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Article
| Open Access
Heat shock protein gp96 drives natural killer cell maturation and anti-tumor immunity by counteracting Trim28 to stabilize Eomes
Natural killer (NK) cell maturation and function are regulated by multiple transcription factors (TF), but detailed molecular insights are scarce. Here the authors show that a TF, Eomes, is important for NK cell responses and cancer surveillance, in which Eomes expression is regulated by gp96 and Trim28 via the ubiquitination and degradation pathways.
- Yuxiu Xu
- , Xin Li
- & Songdong Meng
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Article
| Open Access
Activation of ILC2s through constitutive IFNγ signaling reduction leads to spontaneous pulmonary fibrosis
Idiopathic Pulmonary Fibrosis (IPF) consists of lung inflammation and collagen deposition leading to reduced lung function and non-inducible mouse models are needed. Here the authors show a spontaneous mouse IPF model where Ifngr1-/-Rag2-/- mice show enhanced ILC2 activation and function along with pathology similar to IPF.
- Natsuko Otaki
- , Yasutaka Motomura
- & Kazuyo Moro
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Article
| Open Access
Maternal antibiotic exposure enhances ILC2 activation in neonates via downregulation of IFN1 signaling
Treatment of pregnant animals with antibiotics can have unexpected effects on offspring. Here the authors use mouse models to show that antibiotic treatment of mothers leads to changes in ILC2 phenotype in neonatal lungs accompanied by changes in the microbiota and microbiota derived butyrate.
- Haixu Xu
- , Xianfu Yi
- & Jie Zhou
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Article
| Open Access
Interleukin-9 production by type 2 innate lymphoid cells induces Paneth cell metaplasia and small intestinal remodeling
Paneth cell metaplasia (PCM) typically arises in diseases intrinsic to the gastrointestinal tract; however, whether extra intestinal diseases can trigger PCM and the mechanistic pathway by which PCM develops is unknown. Herein, the authors show in an inducible murine model of chronic myelogenous leukaemia that a systemic inflammatory state can trigger IL-33- mediated IL-9 production that leads to small intestinal remodelling and PCM.
- Chengyin Yuan
- , Aditya Rayasam
- & William R. Drobyski
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Article
| Open Access
Mucosal-associated invariant T cells contribute to suppression of inflammatory myeloid cells in immune-mediated kidney disease
Mucosal associated invariant T (MAIT) cells reside in barrier organs, but their contribution to inflammatory processes in the kidneys is not fully known. Here authors find by single cell RNA sequencing that among the different MAIT cell subtypes found at steady state, a population with MAIT17 signature is expanded in both human crescentic glomerulonephritis and its mouse model, and these cells may play protective role in the disease.
- Ann-Christin Gnirck
- , Marie-Sophie Philipp
- & Jan-Eric Turner
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Article
| Open Access
Themis2 regulates natural killer cell memory function and formation
Innate immunity represents the first line of defence against pathogens, but certain innate cells are capable of memory formation, albeit with different and lesser-known mechanisms than adoptive immune cells. Here authors show that Themis2 regulates both memory NK cell development and function, via distinct downstream pathways.
- Tsukasa Nabekura
- , Elfira Amalia Deborah
- & Akira Shibuya
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Article
| Open Access
A tuft cell - ILC2 signaling circuit provides therapeutic targets to inhibit gastric metaplasia and tumor development
Within gastrointestinal tissues, tuft cells, a rare population of chemo-sensory epithelial cells, can promote the activation of type 2 innate lymphoid cells (ILC2s). Here the authors show that tuft cells and ILC2s are increased during gastric cancer development and that the pharmacologic inhibition of tuft cell derived IL25 or ILC2-produced IL13 reduces gastric tumor growth.
- Ryan N. O’Keefe
- , Annalisa L. E. Carli
- & Michael Buchert
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Article
| Open Access
Perinatal murine cytomegalovirus infection reshapes the transcriptional profile and functionality of NK cells
Early life infections are known to impact and modulate the immune response in later life. Here the authors show that perinatal infection with murine cytomegalovirus results in a modified transcriptional profile and functionality in murine NK cells.
- Carmen Rožmanić
- , Berislav Lisnić
- & Ilija Brizić
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Article
| Open Access
Orai inhibition modulates pulmonary ILC2 metabolism and alleviates airway hyperreactivity in murine and humanized models
The regulation and intracellular transport of Ca2+ in immune cells involves Ca2+ release-activated Ca2+ (CRAC) channels. Here the authors show targeting CRAC components Orai1 and Orai2 modulates pulmonary ILC2 cells altering their metabolism, function and is linked to alleviation of immunopathology in a murine model of allergic airway disease.
- Emily Howard
- , Benjamin P. Hurrell
- & Omid Akbari
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Article
| Open Access
Solar ultraviolet B radiation promotes α-MSH secretion to attenuate the function of ILC2s via the pituitary–lung axis
Allergic asthma is episodic and associated with seasonal changes which may have links with UV exposure levels. Here the authors propose a link between UVB exposure and ILC2 function through α-MSH released from the pituitary gland which accumulates in the serum and alters ILC2 function through the MC5R receptor.
- Yuying Huang
- , Lin Zhu
- & Bing Sun
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Article
| Open Access
Tnpo3 controls splicing of the pre-mRNA encoding the canonical TCR α chain of iNKT cells
iNKT cells recognise glycolipids via their T cell receptors. Here the authors implicate tnpo3 in the regulation of splicing of pre-mRNA encoding cognate TCR α chain for iNKT cells.
- Norimasa Iwanami
- , Andreas S. Richter
- & Thomas Boehm
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Article
| Open Access
MAIT cell inhibition promotes liver fibrosis regression via macrophage phenotype reprogramming
Liver cirrhosis is characterised by extensive fibrosis of the liver, and understanding the underpinning immunological processes is important in designing intervention. Here authors show that Mucosal-Associated Invariant T cells are instrumental to controlling the balance between profibrogenic and restorative macrophages and inhibiting their activation might reverse liver fibrosis.
- Morgane Mabire
- , Pushpa Hegde
- & Sophie Lotersztajn
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Article
| Open Access
Early life gut microbiota sustains liver-resident natural killer cells maturation via the butyrate-IL-18 axis
Liver-resident natural killer cells develop locally and have multiple immunological roles in situ. Here the authors investigate the gut-liver axis and show the impact of the intestinal microbiota on the development of liver-resident natural killer cells.
- Panpan Tian
- , Wenwen Yang
- & Xiaohong Liang
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Article
| Open Access
Maturation and specialization of group 2 innate lymphoid cells through the lung-gut axis
The developmental process of group 2 innate lymphoid cells (ILC2) involves migration between different internal organs. Here the authors show that ILC2s migrate from the lung to the intestine to undergo maturation after treatment with IL-33 and that lung and intestine ILC2s have a different phenotype.
- Min Zhao
- , Fei Shao
- & Shuo Wang
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Article
| Open Access
Interferon regulatory factor 1 (IRF-1) promotes intestinal group 3 innate lymphoid responses during Citrobacter rodentium infection
Innate lymphoid cells (ILC) are involved with different immune responses. Here the authors show that Interferon regulatory factor 1 (IRF1) is important for intestinal ILC3 accumulation during Citrobacter rodentium infection and promotes release of the protective cytokine IL-22 and response to IL-23.
- Angelika Schmalzl
- , Tamara Leupold
- & Stefan Wirtz
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Article
| Open Access
Liver group 2 innate lymphoid cells regulate blood glucose levels through IL-13 signaling and suppression of gluconeogenesis
Besides hepatocytes, resident immune cells of the liver are also contributing to the body’s energy homeostasis. Here authors show that group 2 innate lymphoid cells interact with a specific set of hepatocytes in suppressing gluconeogenesis and regulate blood glucose levels via Interleukin-13 signalling.
- Masanori Fujimoto
- , Masataka Yokoyama
- & Tomoaki Tanaka
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Article
| Open Access
Circular RNA circTmem241 drives group III innate lymphoid cell differentiation via initiation of Elk3 transcription
Innate lymphoid cells (ILC) have been shown to be involved in a range of inflammatory contexts but how their cellular lineage is regulated is not fully established. Here the authors show a role for circular RNA circTmem241 in the differentiation of ILC3 via initiation of Elk3 transcription.
- Nian Liu
- , Jiacheng He
- & Zusen Fan
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Article
| Open Access
In mouse chronic pancreatitis CD25+FOXP3+ regulatory T cells control pancreatic fibrosis by suppression of the type 2 immune response
The function of T regulatory cells in the tissue fibrosis in chronic pancreatitis is not fully understood. Here the authors use a mouse model of chronic pancreatitis to show that Treg cells reduce IL-4 mediated chronic inflammation in the pancreas associated with M2-like macrophages in vivo.
- Juliane Glaubitz
- , Anika Wilden
- & Matthias Sendler
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Article
| Open Access
RNA-binding protein RBM3 intrinsically suppresses lung innate lymphoid cell activation and inflammation partially through CysLT1R
The function of RNA binding proteins within innate lymphoid cells (ILC) has been partially characterised. Here the authors show that RBM3 functions to limit the type 2 immunity promoting activity of ILC2 partially through cysteinyl leukotriene 1 receptor.
- Jana H. Badrani
- , Allyssa N. Strohm
- & Taylor A. Doherty
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Article
| Open Access
Notch, RORC and IL-23 signals cooperate to promote multi-lineage human innate lymphoid cell differentiation
Innate lymphoid cells (ILC) are effector cells that rapidly respond to immune evading stimuli, and despite their functional diversity arise from common precursors. Authors here show how the Notch signalling pathway orchestrates ILC development from circulating human ILC precursors via RORC and its target IL-23R.
- Carys A. Croft
- , Anna Thaller
- & James P. Di Santo
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Article
| Open Access
Cigarette smoke aggravates asthma by inducing memory-like type 3 innate lymphoid cells
Cigarette smoking may exacerbate asthma, but the underlying mechanisms have not been studied extensively in human patients. Here authors show that type 3 innate lymphoid cells with activated phenotypes are found in the sputum and blood of smokers in higher frequencies, which might result in the aggravation of asthma.
- Jongho Ham
- , Jihyun Kim
- & Hye Young Kim
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Article
| Open Access
Re-programming mouse liver-resident invariant natural killer T cells for suppressing hepatic and diabetogenic autoimmunity
Invariant natural killer T (iNKT) cells are tissue-resident immune cells recognizing lipid antigens. Here the authors find that liver, but not lung nor spleen, iNKT cells alter their transcriptome upon systemic treatment of lipid nanoparticles for the induction of regulatory B cells and suppression of liver and pancreas autoimmunity in mouse models.
- Channakeshava Sokke Umeshappa
- , Patricia Solé
- & Pere Santamaria
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Article
| Open Access
Intestinal fibroblastic reticular cell niches control innate lymphoid cell homeostasis and function
Fibroblastic reticular cells (FRCs) support localisation of immune cells in secondary lymphoid tissues but less is known about the lamina propria. Here the authors use scRNA-seq and intestinal infection to characterise FRCs in the intestinal lamina propria and show specialised niches that foster innate lymphoid cells during homeostasis and infection.
- Hung-Wei Cheng
- , Urs Mörbe
- & Burkhard Ludewig
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Article
| Open Access
CHMP2A regulates tumor sensitivity to natural killer cell-mediated cytotoxicity
Genetic alteration can render tumor cells resistant to immune cell-mediated killing. Here based on a genome-wide CRISPR screening, the authors show that expression of CHMP2A confers tumor cell resistance to NK cell-mediated cytotoxicity, mechanistically involving CHMP2A-dependent regulation of extracellular vesicle secretion.
- Davide Bernareggi
- , Qi Xie
- & Dan S. Kaufman
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Article
| Open Access
Psychological stress impairs IL22-driven protective gut mucosal immunity against colonising pathobionts
Altered gut microbiome and exacerbation of symptoms at times of psychological stress are feature characteristics of Crohn’s disease. Here authors show in a mouse model that psychological stress impairs IL-22-dependent protective immunity of the ileal mucosa, which allows invasive bacteria to colonise the gut.
- Christopher R. Shaler
- , Alexandra A. Parco
- & Brian K. Coombes
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Article
| Open Access
CD127+ CD94+ innate lymphoid cells expressing granulysin and perforin are expanded in patients with Crohn’s disease
Phenotypic markers that overlap between ILC1 and NK populations have impacted the robust and specific analysis of these immune cell populations. Employing scRNA sequencing here the authors identify CD127+ CD94+ innate lymphoid cells that express granulysin and perforin and are expanded in patients with Crohn’s disease.
- L. Krabbendam
- , B. A. Heesters
- & H. Spits
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Article
| Open Access
Sequential actions of EOMES and T-BET promote stepwise maturation of natural killer cells
Natural Killer cell development is controlled by two related transcription factors, Eomes and T-bet. Authors show here that while the two factors share a large proportion of their target genes, they regulate distinct developmental processes by differing in their pattern of expression and in their associated co-factors.
- Jiang Zhang
- , Stéphanie Le Gras
- & Thierry Walzer
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Article
| Open Access
Metabolic requirements of NK cells during the acute response against retroviral infection
Metabolic alterations control the fate and function of immune cells in response to infections, but the function of NK cell metabolism in the context of acute viral infections is unclear. Here the authors show that acute NK cell responses to Friend retrovirus involve increased glycolysis and mitochondrial metabolism and require amino acid transport as well as iron sufficiency.
- Elisabeth Littwitz-Salomon
- , Diana Moreira
- & David K. Finlay
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Article
| Open Access
MAIT cells regulate NK cell-mediated tumor immunity
Mucosal-associated invariant T (MAIT) cells facilitate anti-microbial responses, but their functions in cancer protection is unclear. Here the authors show that activated MAIT cells induce an IFN-γ transcriptome in natural killer (NK) cells and enhance NK-dependent anti-cancer immunity in mice, thereby hinting a new avenue for cancer therapy.
- Emma V. Petley
- , Hui-Fern Koay
- & Phillip K. Darcy
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Article
| Open Access
NK cells in hypoxic skin mediate a trade-off between wound healing and antibacterial defence
During wound healing and infection in the skin there is a hypoxic environment involving HIF-1α and NK cells. Here the authors show that NK cells through HIF-1α provide a cross-regulatory balance to provide an adequate antimicrobial defence that can inhibit subsequent wound healing.
- Michal Sobecki
- , Ewelina Krzywinska
- & Christian Stockmann
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Article
| Open Access
PPARɣ drives IL-33-dependent ILC2 pro-tumoral functions
Group 2 innate lymphoid cells (ILC2s) are a component of type 2 immune response recently described to be involved in the regulation of anti-tumor immune responses. Here, the authors show that the expression of the peroxisome proliferator-activated receptor γ (PPAPγ) in human and mouse ILC2 sustains type-2 cytokines secretion and support their pro-tumorigenic role in preclinical cancer models.
- Giuseppe Ercolano
- , Alejandra Gomez-Cadena
- & Camilla Jandus
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Article
| Open Access
CD200–CD200R immune checkpoint engagement regulates ILC2 effector function and ameliorates lung inflammation in asthma
The role of the CD200–CD200R axis in regulating pulmonary inflammation is not completely understood. Here the authors show CD200R is expressed on type 2 innate lymphoid cells (ILC2s), and its engagement by CD200 ameliorates airway hyperreactivity and allergic asthma via inhibition of NF-κB signaling.
- Pedram Shafiei-Jahani
- , Doumet Georges Helou
- & Omid Akbari
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Article
| Open Access
Multiplexed histology analyses for the phenotypic and spatial characterization of human innate lymphoid cells
Innate lymphoid cells (ILCs) are important regulators of biological processes. Here the authors combine multiplexed imaging and computational pipelines to reveal tonsillar IRF4+ ILC3s, and to identify conserved stromal landmarks for ILC localization, thereby providing a platform for future ILC studies.
- Anna Pascual-Reguant
- , Ralf Köhler
- & Anja E. Hauser
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Article
| Open Access
Transcriptome and chromatin landscape of iNKT cells are shaped by subset differentiation and antigen exposure
Invariant natural killer T cells are known to be composed of a number of phenotypic and functionally distinct populations. Here the authors use transcriptomic and epigenomic analysis to further characterize the peripheral iNKT compartment before and after antigenic stimulation.
- Mallory Paynich Murray
- , Isaac Engel
- & Mitchell Kronenberg
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Article
| Open Access
Characterization of the pathoimmunology of necrotizing enterocolitis reveals novel therapeutic opportunities
Necrotizing Enterocolitis (NEC) is an untreatable intestinal disease in infants. Here the authors show that human and experimental mouse NEC is associated with altered toll-like receptor expression in the intestine, enhanced Th17/type 3 polarization in adaptive immune and innate lymphoid cells, dysregulated microbiota, and reduced interleukin-37 signaling.
- Steven X. Cho
- , Ina Rudloff
- & Marcel F. Nold
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Article
| Open Access
DR3 stimulation of adipose resident ILC2s ameliorates type 2 diabetes mellitus
Group 2 innate lymphoid cells (ILC2s) are immune cells present in adipose tissue that contribute to metabolic homeostasis. Here the authors show that Death Receptor 3 (DR3) engagement on ILC2s ameliorates glucose tolerance, protects against insulin-resistance onset and reverses established insulin-resistance.
- Pedram Shafiei-Jahani
- , Benjamin P. Hurrell
- & Omid Akbari
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Article
| Open Access
Single-cell RNA sequencing identifies shared differentiation paths of mouse thymic innate T cells
Innate T cells such as iNKT, MAIT and γδ T cells all develop in the thymus, but their differentiation paths are still unclear. Here, the authors show, using single-cell RNA sequencing, that all three cell types develop via shared and branched differentiation paths that are corroborated by additional results from gene-deficient mice and human liver T cells.
- Minji Lee
- , Eunmin Lee
- & You Jeong Lee
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Article
| Open Access
An inducible circular RNA circKcnt2 inhibits ILC3 activation to facilitate colitis resolution
Type 3 innate lymphoid cells (ILC3) are involved in maintaining gut immune homeostasis. Here the authors identify a circular RNA, circKcnt2, to be induced in ILC3s from inflamed gut, yet circKcnt2 deletion aggravates mouse experimental colitis, thereby implicating circKcnt2 as a potential feedback regulator of ILC3 activation and gut immunity.
- Benyu Liu
- , Buqing Ye
- & Zusen Fan
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Article
| Open Access
PD-1 pathway regulates ILC2 metabolism and PD-1 agonist treatment ameliorates airway hyperreactivity
PD-1 is a checkpoint inhibitory immune receptor that restrains proliferation and effector functions of a variety of cells, including ILC2s. Here the authors present a human PD-1 agonist that limits ILC2-dependent allergic airway disease in humanized mice and provide evidence that PD-1 signaling alters ILC2 function by modulation of cell metabolism.
- Doumet Georges Helou
- , Pedram Shafiei-Jahani
- & Omid Akbari
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Article
| Open Access
Cytokines regulate the antigen-presenting characteristics of human circulating and tissue-resident intestinal ILCs
Murine ILCs can modulate T cell responses in MHCII-dependent manner. Here the authors show that human ILCs process and present antigens and induce T-cell responses upon exposure to IL-1-family cytokines; along with the article by Lehmann et al, this work elucidates how cytokines set context specificity of ILC-T cell crosstalk by regulating ILC antigen presentation.
- Anna Rao
- , Otto Strauss
- & Jenny Mjösberg
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Article
| Open Access
Microbiota-induced tissue signals regulate ILC3-mediated antigen presentation
Group 3 innate lymphoid cells (ILC3s) promote T cell activation in the spleen but suppress it in the gut. Here, the authors show that this distinct regulation is mediated by gut microbiota-induced IL-23 and IFN-γ, respectively, and, along with the article by Rao et al, this work elucidates how cytokines set context specificity of ILC-T cell crosstalk by regulating ILC antigen presentation.
- Frank Michael Lehmann
- , Nicole von Burg
- & Daniela Finke
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Article
| Open Access
c-FLIP is crucial for IL-7/IL-15-dependent NKp46+ ILC development and protection from intestinal inflammation in mice
Innate lymphoid cells (ILC) are important immune cells for maintaining the gut homeostasis. Here the authors show that c-FLIP, an anti-apoptotic molecule, is important for the development of NKP46+ ILC1, including conventional natural killer (cNK) cells, and ILC3, with cNK being more critical for ameliorating intestinal inflammation.
- Ute Bank
- , Katrin Deiser
- & Thomas Schüler
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Article
| Open Access
Distinctive phenotypes and functions of innate lymphoid cells in human decidua during early pregnancy
As an interface between maternal and fetal tissues, decidua hosts immune cells specialized in fostering a successful pregnancy. Here the authors carry out high-dimensional characterization of function, morphology and surface markers of human decidual innate lymphoid cells (ILCs), identifying subsets with features distinct from blood ILC.
- Oisín Huhn
- , Martin A. Ivarsson
- & Francesco Colucci
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Article
| Open Access
TGF-β induces ST2 and programs ILC2 development
TGF-β is thought to be important for group 2 innate lymphoid cell (ILC2) function. Here the authors show that TGF-β drives expression of ST2 specifically in ILC2 progenitors and thereby is also important for the development of ILC2s in the bone marrow.
- Li Wang
- , Jun Tang
- & WanJun Chen
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Article
| Open Access
Heterogeneity of human bone marrow and blood natural killer cells defined by single-cell transcriptome
Natural killer (NK) cells are important innate immune cells with diverse functions. Here the authors use single-cell RNA-sequencing of purified human bone marrow and peripheral blood NK cells to define five populations of NK cells with distinct transcriptomic profile to further our understanding of NK development and heterogeneity.
- Chao Yang
- , Jason R. Siebert
- & Subramaniam Malarkannan
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Article
| Open Access
NK cells are activated and primed for skin-homing during acute dengue virus infection in humans
Here, Zimmer et al. analyze the natural killer (NK) cell response in a patient cohort with acute dengue virus infection showing early NK cell activation and proliferation, and the data suggest that NK cell proliferation depends on IL-18 signaling, and that responding NK cells have a skin-homing phenotype.
- Christine L. Zimmer
- , Martin Cornillet
- & Niklas K. Björkström
Premature skewing of T cell receptor clonality and delayed memory expansion in HIV-exposed infants