Group 2 Innate Lymphoid Cells: Team Players in Regulating Asthma

Type 2 immunity helps protect the host from infection, but it also plays key roles in tissue homeostasis, metabolism, and repair. Unfortunately, inappropriate type 2 immune reactions may lead to allergy and asthma. Group 2 innate lymphoid cells (ILC2s) in the lungs respond rapidly to local environmental cues, such as the release of epithelium-derived type 2 initiator cytokines/alarmins, producing type 2 effector cytokines such as IL-4, IL-5, and IL-13 in response to tissue damage and infection. ILC2s are associated with the severity of allergic asthma, and experimental models of lung inflammation have shown how they act as playmakers, receiving signals variously from stromal and immune cells as well as the nervous system and then disseminating cytokine cues to elicit effector functions and potentiate CD4+ T helper cell activation, both of which characterize the pathology of allergic asthma. Recent breakthroughs identifying stromal- and neuronal-derived microenvironmental cues that regulate ILC2s, along with studies recognizing the potential plasticity of ILC2s, have improved our understanding of the immunoregulation of asthma and opened new avenues for drug discovery. Expected final online publication date for the Annual Review of Immunology, Volume 39 is April 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Non-canonical Activation of Human Group 2 Innate Lymphoid Cells by TLR4 Signaling

10.1101/2020.10.29.361345 ◽

2020 ◽

Author(s):

Li She ◽

Hamad H. Alanazi ◽

Jingwei Wang ◽

Daniel P. Chupp ◽

Yijiang Xu ◽

...

Keyword(s):

Cd40 Ligand ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Large Set ◽

Humanized Mouse Model ◽

Tlr4 Signaling ◽

Type 2 Immunity ◽

Effector Cytokines ◽

Group 2

AbstractGroup 2 innate lymphoid cells (ILC2) are emerging as a critical player in type 2 immunity at barrier sites in response to microbial infections and allergen exposures. Although their classical activators are known to be host epithelial-derived alarmin cytokines IL-33, IL-25 or TSLP, it remains elusive whether ILC2 cells can be activated by directly sensing microbial ligands via pattern-recognition receptors such as toll-like receptors (TLRs). Here we report that toll-like receptor 4 (TLR4) is a potent activating receptor of human ILC2. We found that among many microbial ligands examined, lipopolysaccharides (LPS) from multiple species of Gram-negative bacteria, was found to potently stimulate human, but not murine ILC2, to proliferate and produce massive amounts of type 2 effector cytokines IL-4, IL-5, and IL-13. LPS-activated ILC2 also had greatly enhanced the CD40 ligand (CD154) expression and were able to promote the proliferation and antibody production of human B cells in culture. In a humanized mouse model, LPS activated the adoptively transferred human ILC2 in mouse lungs. Both NF-kB and JAK pathways, but not the IL-33-ST2 pathway, were required for LPS to activate human ILC2. RNA-seq data further revealed that LPS induced a large set of genes overlapped significantly with those induced by IL-33. Collectively, these findings support a non-classical mode of activating human ILC2 cells via the LPS-TLR4 signaling axis. Thus, targeting TLR4 signaling pathway might be developed as a new approach by modulating ILC2 activation in treating various type 2 immunity-associated diseases.

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The transcription factor Bcl11b is specifically expressed in group 2 innate lymphoid cells and is essential for their development

Journal of Experimental Medicine ◽

10.1084/jem.20142318 ◽

2015 ◽

Vol 212 (6) ◽

pp. 865-874 ◽

Cited By ~ 94

Author(s):

Yong Yu ◽

Cui Wang ◽

Simon Clare ◽

Juexuan Wang ◽

Song-Choon Lee ◽

...

Keyword(s):

Transcription Factor ◽

Cell Lineage ◽

Influenza Virus Infection ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Effector Cytokines ◽

Group 2

Group 2 innate lymphoid cells (ILCs), or ILC2s, are a subset of recently identified ILCs, which play important roles in innate immunity by producing type 2 effector cytokines. Several transcription factors have been found to have critical functions in the development of both ILC2s and T cells. We report here that Bcl11b, a transcription factor essential in T cell lineage commitment and maintenance, is specifically expressed in progenitors committed to the ILC2 lineage and is required for ILC2 development. The Bcl11b gene is expressed in ∼28% of ILC progenitors (ILCPs; common helper innate lymphoid progenitors or ILCPs expressing either ID2 or promyelocytic leukemia zinc finger, respectively). Both in vitro and in vivo, these Bcl11b-expressing early ILCPs generate only ILC2s. Inactivation of Bcl11b causes a complete loss of ILC2 development from hematopoietic progenitors, which is confirmed upon immune challenge with either papain administration or influenza virus infection.

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Faculty Opinions recommendation of Type I interferon restricts type 2 immunopathology through the regulation of group 2 innate lymphoid cells.

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

10.3410/f.725957336.793515998 ◽

2016 ◽

Author(s):

Kathryn Wood ◽

Fadi Issa

Keyword(s):

Type I Interferon ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Type I ◽

Group 2

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Faculty Opinions recommendation of Interferon and IL-27 antagonize the function of group 2 innate lymphoid cells and type 2 innate immune responses.

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

10.3410/f.725957335.793513867 ◽

2016 ◽

Author(s):

Toshihiro Nakajima ◽

Hidetoshi Fujita

Keyword(s):

Immune Responses ◽

Innate Lymphoid Cells ◽

Innate Immune ◽

Lymphoid Cells ◽

Innate Immune Responses ◽

Group 2

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Effects of BMP7 produced by group 2 innate lymphoid cells on adipogenesis

International Immunology ◽

10.1093/intimm/dxaa013 ◽

2020 ◽

Vol 32 (6) ◽

pp. 407-419 ◽

Cited By ~ 1

Author(s):

Yurina Miyajima ◽

Kafi N Ealey ◽

Yasutaka Motomura ◽

Miho Mochizuki ◽

Natsuki Takeno ◽

...

Keyword(s):

Lipid Accumulation ◽

Adipocyte Differentiation ◽

Allergic Inflammation ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Brown Adipocytes ◽

Morphogenetic Protein ◽

Group 2

Abstract Group 2 innate lymphoid cells (ILC2s) are type 2 cytokine-producing cells that have important roles in helminth infection and allergic inflammation. ILC2s are tissue-resident cells, and their phenotypes and roles are regulated by tissue-specific environmental factors. While the role of ILC2s in the lung, intestine and bone marrow has been elucidated in many studies, their role in adipose tissues is still unclear. Here, we report on the role of ILC2-derived bone morphogenetic protein 7 (BMP7) in adipocyte differentiation and lipid accumulation. Co-culture of fat-derived ILC2s with pluripotent mesenchymal C3H10T1/2 cells and committed white preadipocyte 3T3-L1 cells resulted in their differentiation to adipocytes and induced lipid accumulation. Co-culture experiments using BMP7-deficient ILC2s revealed that BMP7, produced by ILC2s, induces differentiation into brown adipocytes. Our results demonstrate that BMP7, produced by ILC2s, affects adipocyte differentiation, particularly in brown adipocytes.

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Group 2 Innate Lymphoid Cells: Central Players in a Recurring Theme of Repair and Regeneration

International Journal of Molecular Sciences ◽

10.3390/ijms21041350 ◽

2020 ◽

Vol 21 (4) ◽

pp. 1350 ◽

Cited By ~ 3

Author(s):

Melina Messing ◽

Sia Cecilia Jan-Abu ◽

Kelly McNagny

Keyword(s):

T Regulatory Cells ◽

Inflammatory Responses ◽

Expression Profiles ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Helminth Infections ◽

Neonatal Immunity ◽

Group 2 ◽

Transcription Factor Expression

Innate lymphoid cells (ILCs) are recently discovered innate counterparts to the well-established T helper cell subsets and are most abundant at barrier surfaces, where they participate in tissue homeostasis and inflammatory responses against invading pathogens. Group 2 innate lymphoid cells (ILC2s) share cytokine and transcription factor expression profiles with type-2 helper T cells and are primarily associated with immune responses against allergens and helminth infections. Emerging data, however, suggests that ILC2s are also key regulators in other inflammatory settings; both in a beneficial context, such as the establishment of neonatal immunity, tissue repair, and homeostasis, and in the context of pathological tissue damage and disease, such as fibrosis development. This review focuses on the interactions of ILC2s with stromal cells, eosinophils, macrophages, and T regulatory cells that are common to the different settings in which type-2 immunity has been explored. We further discuss how an understanding of these interactions can reveal new avenues of therapeutic tissue regeneration, where the role of ILC2s is yet to be fully established.

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