Innate Lymphoid Cells: Regulators of Gut Barrier Function and Immune Homeostasis

Innate lymphoid cells (ILCs), identified in the early years of this century as a new class of leukocyte family unlike the B or T lymphocytes, play a unique role bridging the innate and adaptive immune responses in mucosal immunity. Their origin, differentiation, and activation process and functions have caught global interest. Recently, accumulating evidence supports that ILCs are vital regulators for gastrointestinal mucosal homeostasis through interactions with other structural and stromal cells in gut epithelial barriers. This review will explore the functions of ILCs and other cells in maintaining gut homeostasis and feature the crosstalk between ILCs with other cells and potential pharmacotherapy targeting ILCs applicable in intestinal innate immunity.

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Yeats4 drives ILC lineage commitment via activation of Lmo4 transcription

Journal of Experimental Medicine ◽

10.1084/jem.20182363 ◽

2019 ◽

Vol 216 (11) ◽

pp. 2653-2668

Author(s):

Benyu Liu ◽

Liuliu Yang ◽

Xiaoxiao Zhu ◽

Huimu Li ◽

Pingping Zhu ◽

...

Keyword(s):

Bone Marrow ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Lineage Commitment ◽

Rna Pol Ii ◽

Hematopoietic System ◽

Pol Ii ◽

Effector Functions ◽

Lineage Differentiation ◽

Mucosal Homeostasis

Innate lymphoid cells (ILCs) play critical roles in defending infections and maintaining mucosal homeostasis. All ILCs arise from common lymphoid progenitors (CLPs) in bone marrow. However, how CLPs stratify and differentiate into ILC lineages remains elusive. Here, we showed that Yeats4 is highly expressed in ILCs and their progenitors. Yeats4 conditional KO in the hematopoietic system causes decreased numbers of ILCs and impairs their effector functions. Moreover, Yeats4 regulates α4β7+ CLP differentiation toward common helper ILC progenitors (CHILPs). Mechanistically, Yeats4 recruits the Dot1l–RNA Pol II complex onto Lmo4 promoter through recognizing H3K27ac modification to initiate Lmo4 transcription in α4β7+ CLPs. Additionally, Lmo4 deficiency also impairs ILC lineage differentiation and their effector functions. Collectively, the Yeats4–Lmo4 axis is required for ILC lineage commitment.

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Innate Lymphoid Cells in Mucosal Homeostasis, Infections, Autoimmune Disorders, and Tumors

Mucosal Immunology ◽

10.1016/b978-0-12-415847-4.00052-5 ◽

2015 ◽

pp. 1003-1012 ◽

Cited By ~ 1

Author(s):

Marco Colonna ◽

Anja Fuchs ◽

Marina Cella

Keyword(s):

Innate Lymphoid Cells ◽

Autoimmune Disorders ◽

Lymphoid Cells ◽

Mucosal Homeostasis

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Innate Lymphoid Cells in Intestinal Homeostasis and Inflammatory Bowel Disease

International Journal of Molecular Sciences ◽

10.3390/ijms22147618 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7618

Author(s):

Angela Saez ◽

Raquel Gomez-Bris ◽

Beatriz Herrero-Fernandez ◽

Claudia Mingorance ◽

Cristina Rius ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

T Cells ◽

Bowel Disease ◽

Intestinal Inflammation ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Intestinal Homeostasis ◽

Mucosal Homeostasis ◽

Inflammatory Bowel ◽

Chronic Intestinal Inflammation

Inflammatory bowel disease (IBD) is a heterogeneous state of chronic intestinal inflammation of unknown cause encompassing Crohn’s disease (CD) and ulcerative colitis (UC). IBD has been linked to genetic and environmental factors, microbiota dysbiosis, exacerbated innate and adaptive immunity and epithelial intestinal barrier dysfunction. IBD is classically associated with gut accumulation of proinflammatory Th1 and Th17 cells accompanied by insufficient Treg numbers and Tr1 immune suppression. Inflammatory T cells guide innate cells to perpetuate a constant hypersensitivity to microbial antigens, tissue injury and chronic intestinal inflammation. Recent studies of intestinal mucosal homeostasis and IBD suggest involvement of innate lymphoid cells (ILCs). These lymphoid-origin cells are innate counterparts of T cells but lack the antigen receptors expressed on B and T cells. ILCs play important roles in the first line of antimicrobial defense and contribute to organ development, tissue protection and regeneration, and mucosal homeostasis by maintaining the balance between antipathogen immunity and commensal tolerance. Intestinal homeostasis requires strict regulation of the quantity and activity of local ILC subpopulations. Recent studies demonstrated that changes to ILCs during IBD contribute to disease development. A better understanding of ILC behavior in gastrointestinal homeostasis and inflammation will provide valuable insights into new approaches to IBD treatment. This review summarizes recent research into ILCs in intestinal homeostasis and the latest advances in the understanding of the role of ILCs in IBD, with particular emphasis on the interaction between microbiota and ILC populations and functions.

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The transcription factor HIF-1α mediates plasticity of NKp46+ innate lymphoid cells in the gut

Journal of Experimental Medicine ◽

10.1084/jem.20210909 ◽

2022 ◽

Vol 219 (2) ◽

Author(s):

Ewelina Krzywinska ◽

Michal Sobecki ◽

Shunmugam Nagarajan ◽

Julian Zacharjasz ◽

Murtaza M. Tambuwala ◽

...

Keyword(s):

Phenotypic Diversity ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Intestinal Damage ◽

Low Oxygen ◽

Gut Homeostasis ◽

Microenvironmental Factors ◽

Gut Mucosa ◽

Ifn Γ ◽

The Impact

Gut innate lymphoid cells (ILCs) show remarkable phenotypic diversity, yet microenvironmental factors that drive this plasticity are incompletely understood. The balance between NKp46+, IL-22–producing, group 3 ILCs (ILC3s) and interferon (IFN)-γ–producing group 1 ILCs (ILC1s) contributes to gut homeostasis. The gut mucosa is characterized by physiological hypoxia, and adaptation to low oxygen is mediated by hypoxia-inducible transcription factors (HIFs). However, the impact of HIFs on ILC phenotype and gut homeostasis is not well understood. Mice lacking the HIF-1α isoform in NKp46+ ILCs show a decrease in IFN-γ–expressing, T-bet+, NKp46+ ILC1s and a concomitant increase in IL-22–expressing, RORγt+, NKp46+ ILC3s in the gut mucosa. Single-cell RNA sequencing revealed HIF-1α as a driver of ILC phenotypes, where HIF-1α promotes the ILC1 phenotype by direct up-regulation of T-bet. Loss of HIF-1α in NKp46+ cells prevents ILC3-to-ILC1 conversion, increases the expression of IL-22–inducible genes, and confers protection against intestinal damage. Taken together, our results suggest that HIF-1α shapes the ILC phenotype in the gut.

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