The development of innate lymphoid cells requires TOX-dependent generation of a common innate lymphoid cell progenitor

TOX, an evolutionarily conserved member of the HMG-box family of proteins, is essential for the development of various cells of both the innate and adaptive immune system. TOX is required for the development of CD4+T lineage cells in the thymus, including natural killer T and T regulatory cells, as well as development of natural killer cells and fetal lymphoid tissue inducer cells, the latter required for lymph node organogenesis. Recently, we have identified a broader role for TOX in the innate immune system, demonstrating that this nuclear protein is required for generation of bone marrow progenitors that have potential to give rise to all innate lymphoid cells. Innate lymphoid cells, classified according to transcription factor expression and cytokine secretion profiles, derive from common lymphoid progenitors in the bone marrow and require Notch signals for their development. We discuss here the role of TOX in specifying CLP toward an innate lymphoid cell fate and hypothesize a possible role for TOX in regulating Notch gene targets during innate lymphoid cell development.

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Changes in bone marrow innate lymphoid cell subsets in monoclonal gammopathy: target for IMiD therapy

Blood Advances ◽

10.1182/bloodadvances.2017012732 ◽

2017 ◽

Vol 1 (25) ◽

pp. 2343-2347 ◽

Cited By ~ 13

Author(s):

Jithendra Kini Bailur ◽

Sameet Mehta ◽

Lin Zhang ◽

Natalia Neparidze ◽

Terri Parker ◽

...

Keyword(s):

Bone Marrow ◽

Lymphoid Cell ◽

Monoclonal Gammopathy ◽

Cell Function ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Innate Lymphoid Cell ◽

Key Points ◽

And Function

Key Points Altered number, subset composition, and function of bone marrow innate lymphoid cells are early events in monoclonal gammopathies. Pomalidomide therapy leads to reduction in Ikzf1 and Ikzf3 and enhanced human innate lymphoid cell function in vivo.

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Determination of the Fate and Function of Innate Lymphoid Cells Following Adoptive Transfer of Innate Lymphoid Cell Precursors

Methods in Molecular Biology - Type 2 Immunity ◽

10.1007/978-1-4939-7896-0_10 ◽

2018 ◽

pp. 109-119 ◽

Cited By ~ 1

Author(s):

Timothy E. O’Sullivan ◽

Joseph C. Sun

Keyword(s):

Adoptive Transfer ◽

Lymphoid Cell ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Innate Lymphoid Cell ◽

And Function

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G9a regulates group 2 innate lymphoid cell development by repressing the group 3 innate lymphoid cell program

Journal of Experimental Medicine ◽

10.1084/jem.20151646 ◽

2016 ◽

Vol 213 (7) ◽

pp. 1153-1162 ◽

Cited By ~ 18

Author(s):

Frann Antignano ◽

Mitchell Braam ◽

Michael R. Hughes ◽

Alistair L. Chenery ◽

Kyle Burrows ◽

...

Keyword(s):

Lymphoid Cell ◽

Lymphoid Cells ◽

Innate Lymphoid Cell ◽

Genome Wide ◽

Allergic Lung Inflammation ◽

Severe Reduction ◽

Repressive Histone Mark ◽

Lysine Methyltransferase ◽

Group 2 ◽

And Function

Innate lymphoid cells (ILCs) are emerging as important regulators of homeostatic and disease-associated immune processes. Despite recent advances in defining the molecular pathways that control development and function of ILCs, the epigenetic mechanisms that regulate ILC biology are unknown. Here, we identify a role for the lysine methyltransferase G9a in regulating ILC2 development and function. Mice with a hematopoietic cell–specific deletion of G9a (Vav.G9a−/− mice) have a severe reduction in ILC2s in peripheral sites, associated with impaired development of immature ILC2s in the bone marrow. Accordingly, Vav.G9a−/− mice are resistant to the development of allergic lung inflammation. G9a-dependent dimethylation of histone 3 lysine 9 (H3K9me2) is a repressive histone mark that is associated with gene silencing. Genome-wide expression analysis demonstrated that the absence of G9a led to increased expression of ILC3-associated genes in developing ILC2 populations. Further, we found high levels of G9a-dependent H3K9me2 at ILC3-specific genetic loci, demonstrating that G9a-mediated repression of ILC3-associated genes is critical for the optimal development of ILC2s. Together, these results provide the first identification of an epigenetic regulatory mechanism in ILC development and function.

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Non-atopic Neonatal Thymic Innate Lymphoid Cell Subsets (ILC1, ILC2, and ILC3) Identification and the Modulatory Effect of IgG From Dermatophagoides Pteronyssinus (Derp)-Atopic Individuals

Frontiers in Allergy ◽

10.3389/falgy.2021.650235 ◽

2021 ◽

Vol 2 ◽

Author(s):

Thamires Rodrigues de Sousa ◽

Fábio da Ressureição Sgnotto ◽

Beatriz Oliveira Fagundes ◽

Alberto José da Silva Duarte ◽

Jefferson Russo Victor

Keyword(s):

Immune Responses ◽

Lymphoid Cell ◽

Human Lymphocytes ◽

Dermatophagoides Pteronyssinus ◽

Lymphoid Cells ◽

Dust Mites ◽

Innate Lymphoid Cell ◽

Human Thymus ◽

Staining Protocol ◽

Insight Into

Innate lymphoid cells (ILCs) are classified into distinct subsets termed ILC1, ILC2, and ILC3 cells. The existing literature lacks evidence identifying ILCs and their subsets in the human thymus but already demonstrates that they can exert several functions in regulating immune responses. Furthermore, it was already described that IgG's repertoires could modulate lymphocytes' maturation in the human thymus. Here we aimed to identify ILCs subsets in the human thymus and provide insight into the possible modulatory effect of purified IgG on these cells. Thymic tissues were obtained from 12 infants without an allergic background (non-atopic), and a literature-based peripheral ILCs staining protocol was used. Purified IgG was obtained from non-atopic individuals (n-At), atopic individuals reactive to allergens non-related to dust mites (nr-At), and atopic individuals reactive to the mite Dermatophagoides pteronyssinus (Derp-At). As with all tissues in which they have already been detected, thymic ILCs are rare, but we could detect viable ILCs in all tested tissues, which did not occur with the ILC1 subset. ILC2 and ILC3 NKp44+ subsets could be detected in all evaluated thymus, but ILC3 NKp44- subset could not. Next, we observed that Derp-At IgG could induce the expression of ILC2 phenotype, higher levels of IL-13, and lower levels of IL-4 when compared to IgG purified from non-atopic or non-related atopic (atopic to allergens excluding dust mites) individuals. These results contribute to the elucidation of human thymic ILCs and corroborate emerging evidence about IgG's premature effect on allergy development-related human lymphocytes' modulation.

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Innate lymphoid cells and disease tolerance in SARS-CoV-2 infection

10.1101/2021.01.14.21249839 ◽

2021 ◽

Author(s):

Noah J. Silverstein ◽

Yetao Wang ◽

Zachary Manickas-Hill ◽

Claudia C. Carbone ◽

Ann Dauphin ◽

...

Keyword(s):

Hospital Stay ◽

Nk Cells ◽

Lymphoid Cell ◽

Fold Increase ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Morbidity And Mortality ◽

Disease Tolerance ◽

Duration Of Hospital Stay ◽

Age And Sex

AbstractBACKGROUNDRisk of severe coronavirus disease 2019 (COVID-19) increases with age, is greater in males, and is associated with decreased numbers of blood lymphoid cells. Though the reasons for these robust associations are unclear, effects of age and sex on innate and adaptive lymphoid subsets, including on homeostatic innate lymphoid cells (ILCs) implicated in disease tolerance, may underlie the effects of age and sex on COVID-19 morbidity and mortality.METHODSFlow cytometry was used to quantitate subsets of blood lymphoid cells from people infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), comparing those hospitalized with severe COVID-19 (n=40) and those treated as outpatients for less severe disease (n=51). 86 healthy individuals served as controls. The relationship between abundance of specific blood lymphoid cell types, age, sex, hospitalization, duration of hospitalization, and elevation of blood markers for systemic inflammation, was determined using multiple regression.RESULTSAfter accounting for effects of age and sex, hospitalization for COVID-19 was associated with 1.78-fold fewer ILCs (95%CI: 2.34–1.36; p = 4.55 x 10−5) and 2.31-fold fewer CD16+ natural killer (NK) cells (95%CI: 3.1–1.71; p = 1.04 x 10−7), when compared to uninfected controls. Among people infected with SARS-CoV-2, the odds ratio for hospitalization, adjusted for age, sex, and duration of symptoms, was 0.413 (95%CI: 0.197–0.724; p = 0.00691) for every 2-fold increase in ILCs. In addition, higher ILC abundance was associated with less time spent in the hospital and lower levels of blood markers associated with COVID-19 severity: each two-fold increase in ILC abundance was associated with a 9.38 day decrease in duration of hospital stay (95% CI: 15.76–3.01; p= 0.0054), and decrease in blood C-reactive protein (CRP) by 46.29 mg/L (95% CI: 71.34–21.24; p = 6.25 x 10−4), erythrocyte sedimentation rate (ESR) by 11.04 mm/h (95% CI: 21.94–0.13; p = 0.047), and the fibrin degradation product D-dimer by 1098.52 ng/mL (95% CI: 1932.84–264.19; p = 0.011).CONCLUSIONSBoth ILCs and NK cells were depleted in the blood of people hospitalized for severe COVID-19, but, among lymphoid cell subsets, only ILC abundance was independently associated with the need for hospitalization, duration of hospital stay, and severity of inflammation. These results indicate that, by promoting disease tolerance, homeostatic ILCs protect against morbidity and mortality in SARS-CoV-2 infection, and suggest that reduction in the number of ILCs with age and in males accounts for the increased risk of severe COVID-19 in these demographic groups.

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Circulating innate lymphoid cell subtypes and altered cytokine profiles following an atherogenic high-fat diet

Innate Immunity ◽

10.1177/17534259211053634 ◽

2021 ◽

pp. 175342592110536

Author(s):

Vuyolwethu Mxinwa ◽

Phiwayinkosi V. Dludla ◽

Tawanda M. Nyambuya ◽

Bongani B. Nkambule

Keyword(s):

Total Cholesterol ◽

Lymphoid Cell ◽

High Fat Diet ◽

Adaptive Immune Response ◽

Lymphoid Cells ◽

High Fat ◽

Innate Lymphoid Cell ◽

Insulin Levels ◽

Cytokine Profiles ◽

Cholesterol Levels

Impaired Glc tolerance and hyperinsulinemia are a hallmark of type 2 diabetes (T2D) and are associated with an altered innate and adaptive immune response. In this study, we used a high-fat diet (HFD)-induced model of pre-diabetes to explore the pathological implications of altered innate lymphoid cell (ILC) profiles in a state of impaired Glc tolerance. Sixteen male C57BL/6 mice were randomized to receive two experimental diets ( n = 8 per group), low-fat (LFD), and HFD for 8–13 wk. We evaluated the levels of circulating innate lymphoid cells and their respective cytokines following HFD-feeding. The HFD group had impaired Glc tolerance, elevated insulin levels, and increased total cholesterol levels. Notably, the levels of circulating ILC1s were elevated following 13 wk of HFD-feeding. Moreover, the levels of TNF-α were decreased, but there were no changes in IFN-γ levels. Lastly, the levels of circulating ILC2s and ILC3s were comparable between the HFD and LFD group. The findings demonstrated that short-term HFD-feeding increases postprandial blood Glc, total cholesterol and insulin levels. However, the metabolic changes did not alter ILC2 and ILC3 levels and their respective cytokine profiles.

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Crosstalk between enterocytes and innate lymphoid cells drives early IFN-g-mediated control of Cryptosporidium

10.1101/2021.03.13.435244 ◽

2021 ◽

Author(s):

Jodi Gullicksrud ◽

Adam Sateriale ◽

Julie B. Engiles ◽

Alexis Gibson ◽

Sebastian Shaw ◽

...

Keyword(s):

Dendritic Cells ◽

Child Mortality ◽

Lymphoid Cell ◽

Intestinal Parasite ◽

Transcriptional Profiling ◽

Lymphoid Cells ◽

Major Contributor ◽

Parasite Control ◽

Innate Lymphoid Cell ◽

Control Loss

The intestinal parasite, Cryptosporidium, is a major contributor to global child mortality and causes opportunistic infection in immune deficient individuals. Innate resistance to Cryptosporidium, which specifically invades enterocytes, is dependent on the production of IFN-g, yet whether enterocytes contribute to parasite control is poorly understood. In this study, utilizing the natural mouse pathogen, Cryptosporidium tyzzeri, we show that epithelial-derived IL-18 synergized with IL-12 to stimulate innate lymphoid cell (ILC) production of IFN-g. This innate IFN-g was required for early parasite control. Loss of STAT1 in enterocytes, but not dendritic cells or macrophages, antagonized early parasite control. Transcriptional profiling of enterocytes from infected mice identified an IFN-g signature and enrichment of anti-microbial effectors like IDO, GBP and IRG. Deletion experiments identified a role for Irgm1/m3 in parasite control. Thus, enterocytes promote ILC production of IFN-g that acts on enterocytes to restrict the growth of C. tyzzeri.

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Living with Yourself: Innate Lymphoid Cell Immunometabolism

Cells ◽

10.3390/cells9020334 ◽

2020 ◽

Vol 9 (2) ◽

pp. 334 ◽

Cited By ~ 5

Author(s):

Marion Rolot ◽

Timothy E. O’Sullivan

Keyword(s):

Immune System ◽

Recent Work ◽

Lymphoid Cell ◽

Environmental Changes ◽

Lymphoid Cells ◽

Innate Lymphoid Cell ◽

Open Questions ◽

Health And Disease ◽

Host Metabolism ◽

Support Evidence

Innate lymphoid cells (ILCs) are tissue-resident sentinels of the immune system that function to protect local tissue microenvironments against pathogens and maintain homeostasis. However, because ILCs are sensitively tuned to perturbations within tissues, they can also contribute to host pathology when critical activating signals become dysregulated. Recent work has demonstrated that the crosstalk between ILCs and their environment has a significant impact on host metabolism in health and disease. In this review, we summarize studies that support evidence for the ability of ILCs to influence tissue and systemic metabolism, as well as how ILCs can be regulated by environmental changes in systemic host metabolism. We also highlight studies demonstrating how ILC- intrinsic metabolism influences their activation, proliferation, and homeostasis. Finally, this review discusses the challenges and open questions in the rapidly expanding field of ILCs and immunometabolism.

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