Differentiation and function of group 3 innate lymphoid cells, from embryo to adult

CCR6− group 3 innate lymphoid cells (ILC3s) are mediators of intestinal immunity and barrier function that possess the capacity to acquire type 1 effector features and fully convert into ILC1s. The molecular mechanisms governing such plasticity are undefined. Here, we identified c-Maf as an essential regulator of ILC3 homeostasis and plasticity that limits physiological ILC1 conversion. Phenotypic analysis of effector status in Maf-deficient CCR6− ILC3s, coupled with evaluation of global changes in transcriptome, chromatin accessibility, and transcription factor motif enrichment, revealed that c-Maf enforces ILC3 identity. c-Maf promoted ILC3 accessibility and supported RORγt activity and expression of type 3 effector genes. Conversely, c-Maf antagonized type 1 programming, largely through restraint of T-bet expression and function. Mapping of the dynamic changes in chromatin landscape accompanying CCR6− ILC3 development and ILC1 conversion solidified c-Maf as a gatekeeper of type 1 regulatory transformation and a controller of ILC3 fate.

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DOCK8 controls survival of group 3 innate lymphoid cells in the gut through Cdc42 activation

International Immunology ◽

10.1093/intimm/dxaa066 ◽

2020 ◽

Author(s):

Ryosuke Aihara ◽

Kazufumi Kunimura ◽

Mayuki Watanabe ◽

Takehito Uruno ◽

Nana Yamane ◽

...

Keyword(s):

Fetal Liver ◽

Underlying Mechanism ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Brdu Incorporation ◽

Catalytic Center ◽

Dock8 Deficiency ◽

Group 3 ◽

And Function

Abstract Innate lymphoid cells (ILCs) are a family of developmentally related leukocytes that rapidly secrete polarized sets of cytokines to combat infection and promote tissue repair at mucosal barriers. Among them, group 3 ILCs (ILC3s) play an important role in maintenance of the gut homeostasis by producing IL-22, and their development and function critically depend on the transcription factor RORγt. Although recent evidence indicates that RORγt+ ILC3s are reduced in the gut in the absence of the Cdc42 activator DOCK8 (dedicator of cytokinesis 8), the underlying mechanism remains unclear. We found that genetic deletion of Dock8 in RORγt+-lineage cells markedly reduced ILC3s in the lamina propria of the small intestine. By analyzing BrdU incorporation, it was revealed that DOCK8 deficiency did not affect the cell proliferation. Furthermore, when lineage marker-negative (Lin–) α4β7+ CD127+ RORγt– fetal liver cells were cultured with OP9 stromal cells in the presence of stem cell factor (SCF) and IL-7 in vitro, RORγt+ ILC3s normally developed irrespective of DOCK8 expression. However, DOCK8-deficient ILC3s exhibited a severe defect in survival of ILC3s under the condition with or without IL-7. Similar defects were observed when we analyzed Dock8VAGR mice having mutations in the catalytic center of DOCK8, thereby failing to activate Cdc42. Thus, DOCK8 acts in cell-autonomous manner to control survival of ILC3s in the gut through Cdc42 activation.

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The Role of Group 3 Innate Lymphoid Cells in Lung Infection and Immunity

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.586471 ◽

2021 ◽

Vol 11 ◽

Author(s):

Dan Yang ◽

Xinning Guo ◽

Tingxuan Huang ◽

Chuntao Liu

Keyword(s):

Respiratory Infections ◽

Inflammatory Diseases ◽

Pulmonary Inflammation ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Intestinal Immunity ◽

Group 3 ◽

Underlying Mechanisms ◽

And Function ◽

Pathogen Clearance

The lung is constantly exposed to environmental particulates such as aeroallergens, pollutants, or microorganisms and is protected by a poised immune response. Innate lymphoid cells (ILCs) are a population of immune cells found in a variety of tissue sites, particularly barrier surfaces such as the lung and the intestine. ILCs play a crucial role in the innate immune system, and they are involved in the maintenance of mucosal homeostasis, inflammation regulation, tissue remodeling, and pathogen clearance. In recent years, group 3 innate lymphoid cells (ILC3s) have emerged as key mediators of mucosal protection and repair during infection, mainly through IL-17 and IL-22 production. Although research on ILC3s has become focused on the intestinal immunity, the biology and function of pulmonary ILC3s in the pathogenesis of respiratory infections and in the development of chronic pulmonary inflammatory diseases remain elusive. In this review, we will mainly discuss how pulmonary ILC3s act on protection against pathogen challenge and pulmonary inflammation, as well as the underlying mechanisms.

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Faculty Opinions recommendation of Anti-microbial Functions of Group 3 Innate Lymphoid Cells in Gut-Associated Lymphoid Tissues Are Regulated by G-Protein-Coupled Receptor 183.

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

10.3410/f.733518679.793551473 ◽

2018 ◽

Author(s):

Andrea Reboldi

Keyword(s):

G Protein ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Lymphoid Tissues ◽

G Protein Coupled Receptor ◽

Group 3 ◽

G Protein Coupled

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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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Gata3 drives development of RORγt+ group 3 innate lymphoid cells

Journal of Experimental Medicine ◽

10.1084/jem.20131038 ◽

2014 ◽

Vol 211 (2) ◽

pp. 199-208 ◽

Cited By ~ 152

Author(s):

Nicolas Serafini ◽

Roel G.J. Klein Wolterink ◽

Naoko Satoh-Takayama ◽

Wei Xu ◽

Christian A.J. Vosshenrich ◽

...

Keyword(s):

T Cell ◽

Fetal Liver ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

T Cell Subsets ◽

Mucosal Barrier ◽

Hematopoietic Stem ◽

Mucosal Surfaces ◽

Gata3 Expression ◽

Group 3

Group 3 innate lymphoid cells (ILC3) include IL-22–producing NKp46+ cells and IL-17A/IL-22–producing CD4+ lymphoid tissue inducerlike cells that express RORγt and are implicated in protective immunity at mucosal surfaces. Whereas the transcription factor Gata3 is essential for T cell and ILC2 development from hematopoietic stem cells (HSCs) and for IL-5 and IL-13 production by T cells and ILC2, the role for Gata3 in the generation or function of other ILC subsets is not known. We found that abundant GATA-3 protein is expressed in mucosa-associated ILC3 subsets with levels intermediate between mature B cells and ILC2. Chimeric mice generated with Gata3-deficient fetal liver hematopoietic precursors lack all intestinal RORγt+ ILC3 subsets, and these mice show defective production of IL-22 early after infection with the intestinal pathogen Citrobacter rodentium, leading to impaired survival. Further analyses demonstrated that ILC3 development requires cell-intrinsic Gata3 expression in fetal liver hematopoietic precursors. Our results demonstrate that Gata3 plays a generalized role in ILC lineage determination and is critical for the development of gut RORγt+ ILC3 subsets that maintain mucosal barrier homeostasis. These results further extend the paradigm of Gata3-dependent regulation of diversified innate ILC and adaptive T cell subsets.

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