Nfil3 is crucial for development of innate lymphoid cells and host protection against intestinal pathogens

The bZIP transcription factor Nfil3 (also known as E4BP4) is required for the development of natural killer (NK) cells and type 1 innate lymphoid cells (ILC1s). We find that Nfil3 plays a critical role in the development of other mucosal tissue-associated innate lymphocytes. Type 3 ILCs (ILC3s), including lymphoid tissue inducer (LTi)–like cells, are severely diminished in both numbers and function in Nfil3-deficient mice. Using mixed bone marrow chimeric mice, we demonstrate that Nfil3 is critical for normal development of gut-associated ILC3s in a cell-intrinsic manner. Furthermore, Nfil3 deficiency severely compromises intestinal innate immune defense against acute bacterial infection with Citrobacter rodentium and Clostridium difficile. Nfil3 deficiency resulted in a loss of the recently identified ILC precursor, yet conditional ablation of Nfil3 in the NKp46+ ILC3 subset did not perturb ILC3 numbers, suggesting that Nfil3 is required early during ILC3 development but not for lineage maintenance. Lastly, a marked defect in type 2 ILCs (ILC2s) was also observed in the lungs and visceral adipose tissue of Nfil3-deficient mice, revealing a general requirement for Nfil3 in the development of all ILC lineages.

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NKR-P1B Receptor Expression and Function in the Different Innate Lymphoid Cells of the Lung

Inquiry@Queen's Undergraduate Research Conference Proceedings ◽

10.24908/iqurcp.14703 ◽

2021 ◽

Author(s):

Lucas Vajko

Keyword(s):

Nk Cell ◽

Γδ T Cells ◽

Bronchial Epithelium ◽

Lung Parenchyma ◽

Recognition System ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Receptor Expression ◽

And Function ◽

Deficient Mice

Group 2 innate lymphoid cells (ILC2) are the majority of ILCs in murine lungs at steady state. ILC2s are the main producer of type-2-cytokines, IL-4, IL-5, IL-9, IL-13, and amphiregulin, playing key roles in lung tissue homeostasis, airway responses to pathogens and allergens, and in cancer-related defenses. ILC functions are regulated by cell surface receptors. NKR-P1B is an inhibitory receptor, which recognizes C-type lectin-related protein (Clr-b) as its ligand. NKR-P1B is expressed on subsets of natural killer cells, ILC2, ILC3, γδ T cells, macrophages and dendritic cells in a tissue-specific manner and regulates NK cell and ILC3 functions in the gut. Expression and function of NKR-P1B in the lung ILC populations is unexplored. Moreover, Clr-b, the ligand for NKR-P1B, is expressed in the bronchial epithelium, endothelial cells and in lung parenchyma, but its role in immune regulation in the lung is unknown. We hypothesize that ILC2s in the lung express NKR-P1B, and their function is regulated by the NKR-P1B:Clr-b recognition system. Using wild-type (WT) and NKR-P1B-deficient mice, we study the expression of NKR-P1B on lung ILC2, and the function of NKR-P1B:Clr-b recognition system in ILC2 development and function. We compare the phenotype, frequency, numbers and cytokine production by ILC2s upon stimulation between WT and NKR-P1B-deficient mice using antibody staining and flow cytometry analysis. This study will reveal the role of NKR-P1B as a model system for its human homolog, NKR-P1A, in the regulation of ILC development and function, advancing our understanding of how immune responses in the lung are regulated.

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Roles of Type 1, 2, and 3 Innate Lymphoid Cells in Herpes Simplex Virus 1 InfectionIn VitroandIn Vivo

Journal of Virology ◽

10.1128/jvi.00523-19 ◽

2019 ◽

Vol 93 (13) ◽

Cited By ~ 3

Author(s):

Satoshi Hirose ◽

Shaohui Wang ◽

Kati Tormanen ◽

Yizhou Wang ◽

Jie Tang ◽

...

Keyword(s):

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Wild Type ◽

Herpes Simplex Virus 1 ◽

Type 3 ◽

Deficient Mice ◽

Hsv 1

ABSTRACTInnate lymphoid cells (ILCs) play important roles in host defense and inflammation. They are classified into three distinct groups based on their cytokine and chemokine secretion patterns and transcriptome profiles. Here, we show that ILCs isolated from mice can be infected with herpes simplex virus 1 (HSV-1) but that subsequent replication of the virus is compromised. After infection, type 2 ILCs expressed significantly higher levels of granulocyte colony-stimulating factor (G-CSF), interleukin 1α (IL-1α), IL-6, IL-9, RANTES, tumor necrosis factor alpha (TNF-α), CXCL1, CXCL2, CXCL10, CCL3, and CCL4 than infected type 1 or type 3 ILCs. Transcriptome-sequencing (RNA-seq) analysis of the ILCs 24 h after HSV-1 infection revealed that 77 herpesvirus genes were detected in the infected type 3 ILCs, whereas only 11 herpesvirus genes were detected in infected type 1 ILCs and 27 in infected type 2 ILCs. Compared with uninfected cells, significant upregulation of over 4,000 genes was seen in the HSV-1-infected type 3 ILCs, whereas 414 were upregulated in the infected type 1 ILCs and 128 in the infected type 2 ILCs. In contrast, in all three cell types, only a limited number of genes were significantly downregulated. Type 1, type 2, and type 3 ILC-deficient mice were used to gain insights into the effects of the ILCs on the outcome of ocular HSV-1 infection. No significant differences were found on comparison with similarly infected wild-type mice or on comparison of the three strains of deficient mice in terms of virus replication in the eyes, levels of corneal scarring, latency-reactivation in the trigeminal ganglia, or T-cell exhaustion. Although there were no significant differences in the survival rates of infected ILC-deficient mice and wild-type mice, there was significantly reduced survival of the infected type 1 or type 3 ILC-deficient mice compared with type 2 ILC-deficient mice. Adoptive transfer of wild-type T cells did not alter survival or any other parameters tested in the infected mice. Our results indicate that type 1, 2, and 3 ILCs respond differently to HSV-1 infectionin vitroand that the absence of type 1 or type 3, but not type 2, ILCs affects the survival of ocularly infected mice.IMPORTANCEIn this study, we investigated for the first time what roles, if any, innate lymphoid cells (ILCs) play in HSV-1 infection. Analysis of isolated ILCsin vitrorevealed that all three subtypes could be infected with HSV-1 but that they were resistant to replication. The expression profiles of HSV-1-induced cytokines/chemokines and cellular and viral genes differed among the infected type 1, 2, and 3 ILCsin vitro. While ILCs play no role or a redundant role in the outcomes of latency-reactivation in infected mice, absence of type 1 and type 3, but not type 2, ILCs affects the survival of infected mice.

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Faculty Opinions recommendation of Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718318309.793493012 ◽

2014 ◽

Author(s):

Troy Randall ◽

Maria de la Luz Garcia-Hernandez ◽

Javier Rangel-Moreno

Keyword(s):

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Type 3

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Vitamin D/Vitamin D Receptor Signaling is Required for Normal Development and Function of Group Innate Lymphoid Cells in the Gut

SSRN Electronic Journal ◽

10.2139/ssrn.3280247 ◽

2018 ◽

Author(s):

Lei He ◽

Mingxia Zhou ◽

Yan Chun Li

Keyword(s):

Vitamin D ◽

Vitamin D Receptor ◽

Normal Development ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Receptor Signaling ◽

And Function

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Transcription Factors in the Development and Function of Group 2 Innate Lymphoid Cells

International Journal of Molecular Sciences ◽

10.3390/ijms20061377 ◽

2019 ◽

Vol 20 (6) ◽

pp. 1377 ◽

Cited By ~ 6

Author(s):

Takashi Ebihara ◽

Ichiro Taniuchi

Keyword(s):

Transcription Factors ◽

Physiological State ◽

Allergic Inflammation ◽

Allergic Diseases ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Th2 Cytokine ◽

Parasitic Worm ◽

Group 2 ◽

And Function

Group 2 innate lymphoid cells (ILC2s) are tissue-resident cells and are a major source of innate TH2 cytokine secretion upon allergen exposure or parasitic-worm infection. Accumulating studies have revealed that transcription factors, including GATA-3, Bcl11b, Gfi1, RORα, and Ets-1, play a role in ILC2 differentiation. Recent reports have further revealed that the characteristics and functions of ILC2 are influenced by the physiological state of the tissues. Specifically, the type of inflammation strongly affects the ILC2 phenotype in tissues. Inhibitory ILC2s, memory-like ILC2s, and ex-ILC2s with ILC1 features acquire their characteristic properties following exposure to their specific inflammatory environment. We have recently reported a new ILC2 population, designated as exhausted-like ILC2s, which emerges after a severe allergic inflammation. Exhausted-like ILC2s are featured with low reactivity and high expression of inhibitory receptors. Therefore, for a more comprehensive understanding of ILC2 function and differentiation, we review the recent knowledge of transcriptional regulation of ILC2 differentiation and discuss the roles of the Runx transcription factor in controlling the emergence of exhausted-like ILC2s. The concept of exhausted-like ILC2s sheds a light on a new aspect of ILC2 biology in allergic diseases.

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Type 3 innate lymphoid cells induce proliferation of CD94+ natural killer cells

Journal of Allergy and Clinical Immunology ◽

10.1016/j.jaci.2017.03.033 ◽

2017 ◽

Vol 140 (4) ◽

pp. 1156-1159.e7 ◽

Cited By ~ 1

Author(s):

Shuo Li ◽

Hideaki Morita ◽

Beate Rückert ◽

Tadech Boonpiyathad ◽

Avidan Neumann ◽

...

Keyword(s):

Natural Killer Cells ◽

Natural Killer ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Killer Cells ◽

Type 3

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Transcriptional regulatory networks that promote and restrict identities and functions of intestinal innate lymphoid cells

10.1101/465435 ◽

2018 ◽

Cited By ~ 1

Author(s):

Maria Pokrovskii ◽

Jason A. Hall ◽

David E. Ochayon ◽

Ren Yi ◽

Natalia S. Chaimowitz ◽

...

Keyword(s):

Regulatory Networks ◽

Inflammatory Diseases ◽

Innate Lymphoid Cells ◽

Chromatin Accessibility ◽

Immune Defense ◽

Lymphoid Cells ◽

Transcriptional Regulatory Networks ◽

Transcriptional Regulatory

SummaryInnate lymphoid cells (ILCs) can be subdivided into several distinct cytokine-secreting lineages that promote tissue homeostasis and immune defense but also contribute to inflammatory diseases. Accumulating evidence suggests that ILCs, similarly to other immune populations, are capable of phenotypic and functional plasticity in response to infectious or environmental stimuli. Yet the transcriptional circuits that control ILC identity and function are largely unknown. Here we integrate gene expression and chromatin accessibility data to infer transcriptional regulatory networks within intestinal type 1, 2, and 3 ILCs. We predict the “core” sets of transcription-factor (TF) regulators driving each ILC subset identity, among which only a few TFs were previously known. To assist in the interpretation of these networks, TFs were organized into cooperative clusters, or modules that control gene programs with distinct functions. The ILC network reveals extensive alternative-lineage-gene repression, whose regulation may explain reported plasticity between ILC subsets. We validate new roles for c-MAF and BCL6 as regulators affecting the type 1 and type 3 ILC lineages. Manipulation of TF pathways identified here might provide a novel means to selectively regulate ILC effector functions to alleviate inflammatory disease or enhance host tolerance to pathogenic microbes or noxious stimuli. Our results will enable further exploration of ILC biology, while our network approach will be broadly applicable to identifying key cell state regulators in otherin vivocell populations.

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