IL-33 promotes the egress of group 2 innate lymphoid cells from the bone marrow

Group 2 innate lymphoid cells (ILC2s) are effector cells within the mucosa and key participants in type 2 immune responses in the context of allergic inflammation and infection. ILC2s develop in the bone marrow from common lymphoid progenitor cells, but little is known about how ILC2s egress from the bone marrow for hematogenous trafficking. In this study, we identified a critical role for IL-33, a hallmark peripheral ILC2-activating cytokine, in promoting the egress of ILC2 lineage cells from the bone marrow. Mice lacking IL-33 signaling had normal development of ILC2s but retained significantly more ILC2 progenitors in the bone marrow via augmented expression of CXCR4. Intravenous injection of IL-33 or pulmonary fungal allergen challenge mobilized ILC2 progenitors to exit the bone marrow. Finally, IL-33 enhanced ILC2 trafficking to the lungs in a parabiosis mouse model of tissue disruption and repopulation. Collectively, these data demonstrate that IL-33 plays a critical role in promoting ILC2 egress from the bone marrow.

Download Full-text

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.

Download Full-text

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.

Download Full-text

T-bet fate mapping identifies a novel ILC1-ILC2 subset in vivo

10.1101/2020.08.21.261073 ◽

2020 ◽

Author(s):

J-H Schroeder ◽

N Garrido-Mesa ◽

T Zabinski ◽

AL Gallagher ◽

L Campbell ◽

...

Keyword(s):

Transcription Factors ◽

Immune Responses ◽

Critical Role ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Fate Mapping ◽

Functional Roles ◽

Mucosal Surfaces ◽

Group 2

ABSTRACTInnate lymphoid cells (ILC) play a critical role in regulating immune responses at mucosal surfaces. Various subsets exist resembling T cell lineages defined by the expression of specific transcription factors. Thus, T-bet is expressed in ILC1 and Th1 cells. In order to further understand the functional roles of T-bet in ILC, we generated a fate-mapping mouse model that permanently marks cells and their progeny that are expressing, or have ever expressed T-bet. Here we have identified and characterised a novel ILC with characteristics of ILC1 and ILC2 that are “fate-mapped” for T-bet expression and arise early in neonatal life prior to establishment of a mature microbiome. These ILC1-ILC2 cells are critically dependent on T-bet and are able to express type 1 and type 2 cytokines at steady state, but not in the context of inflammation. These findings refine our understanding of ILC lineage regulation and stability and have important implications for the understanding of ILC biology at mucosal surfaces.SUMMARYInnate lymphoid cells (ILC) play a critical role in regulating immune responses at mucosal surfaces. Three distinct ILC groups have been described according to expression of subset defining transcription factors and other markers. In this study we characterize a novel ILC subset with characteristics of group 1 and group 2 ILC in vivo.

Download Full-text

An ST2-dependent role of bone marrow-derived group 2 innate lymphoid cells in pulmonary fibrosis

The Journal of Pathology ◽

10.1002/path.5092 ◽

2018 ◽

Vol 245 (4) ◽

pp. 399-409 ◽

Cited By ~ 10

Author(s):

Yuyue Zhao ◽

Francina Gonzalez De Los Santos ◽

Zhe Wu ◽

Tianju Liu ◽

Sem H Phan

Keyword(s):

Bone Marrow ◽

Pulmonary Fibrosis ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Group 2

Download Full-text

Innate Lymphoid Cells in Human Pregnancy

Frontiers in Immunology ◽

10.3389/fimmu.2020.551707 ◽

2020 ◽

Vol 11 ◽

Author(s):

João Mendes ◽

Ana Luísa Areia ◽

Paulo Rodrigues-Santos ◽

Manuel Santos-Rosa ◽

Anabela Mota-Pinto

Keyword(s):

Nk Cells ◽

Innate Lymphoid Cells ◽

Adverse Outcomes ◽

Lymphoid Cells ◽

Perinatal Medicine ◽

Effector Cells ◽

Human Pregnancy ◽

Group 3 ◽

Group 2 ◽

In Pregnancy

Innate lymphoid cells (ILCs) are a new set of cells considered to be a part of the innate immune system. ILCs are classified into five subsets (according to their transcription factors and cytokine profile) as natural killer cells (NK cells), group 1 ILCs, group 2 ILCs, group 3 ILCs, and lymphoid tissue inducers (LTi). Functionally, these cells resemble the T helper population but lack the expression of recombinant genes, which is essential for the formation of T cell receptors. In this work, the authors address the distinction between peripheral and decidual NK cells, highlighting their diversity in ILC biology and its relevance to human pregnancy. ILCs are effector cells that are important in promoting immunity, inflammation, and tissue repair. Recent studies have directed their attention to ILC actions in pregnancy. Dysregulation or expansion of pro-inflammatory ILC populations as well as abnormal tolerogenic responses may directly interfere with pregnancy, ultimately resulting in pregnancy loss or adverse outcomes. In this review, we characterize these cells, considering recent findings and addressing knowledge gaps in perinatal medicine in the context of ILC biology. Moreover, we discuss the relevance of these cells not only to the process of immune tolerance, but also in disease.

Download Full-text

Activation of group 2 innate lymphoid cells after allergen challenge in asthmatic patients

Journal of Allergy and Clinical Immunology ◽

10.1016/j.jaci.2019.01.027 ◽

2019 ◽

Vol 144 (1) ◽

pp. 61-69.e7 ◽

Cited By ~ 15

Author(s):

Carla Winkler ◽

Thomas Hochdörfer ◽

Elisabeth Israelsson ◽

Annemarie Hasselberg ◽

Anders Cavallin ◽

...

Keyword(s):

Allergen Challenge ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Asthmatic Patients ◽

Group 2

Download Full-text

Exhausted-like Group 2 Innate Lymphoid Cells in Chronic Allergic Inflammation

Trends in Immunology ◽

10.1016/j.it.2019.10.007 ◽

2019 ◽

Vol 40 (12) ◽

pp. 1095-1104 ◽

Cited By ~ 1

Author(s):

Takashi Ebihara ◽

Ichiro Taniuchi

Keyword(s):

Allergic Inflammation ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Group 2

Download Full-text

IL-12 drives functional plasticity of human group 2 innate lymphoid cells

Journal of Experimental Medicine ◽

10.1084/jem.20151750 ◽

2016 ◽

Vol 213 (4) ◽

pp. 569-583 ◽

Cited By ~ 144

Author(s):

Ai Ing Lim ◽

Silvia Menegatti ◽

Jacinta Bustamante ◽

Lionel Le Bourhis ◽

Matthieu Allez ◽

...

Keyword(s):

Ex Vivo ◽

Human Peripheral Blood ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Functional Plasticity ◽

Effector Cells ◽

Ifn Γ ◽

Group 2 ◽

Innate Effector

Group 2 innate lymphoid cells (ILC2) include IL-5– and IL-13–producing CRTh2+CD127+ cells that are implicated in early protective immunity at mucosal surfaces. Whereas functional plasticity has been demonstrated for both human and mouse ILC3 subsets that can reversibly give rise to IFN-γ–producing ILC1, plasticity of human or mouse ILC2 has not been shown. Here, we analyze the phenotypic and functional heterogeneity of human peripheral blood ILC2. Although subsets of human CRTh2+ ILC2 differentially express CD117 (c-kit receptor), some ILC2 surface phenotypes are unstable and can be modulated in vitro. Surprisingly, human IL-13+ ILC2 can acquire the capacity to produce IFN-γ, thereby generating plastic ILC2. ILC2 cultures demonstrated that IFN-γ+ ILC2 clones could be derived and were stably associated with increased T-BET expression. The inductive mechanism for ILC2 plasticity was mapped to the IL-12–IL-12R signaling pathway and was confirmed through analysis of patients with Mendelian susceptibility to mycobacterial disease due to IL-12Rβ1 deficiencies that failed to generate plastic ILC2. We also detected IL-13+IFN-γ+ ILC2 ex vivo in intestinal samples from Crohn’s disease patients. These results demonstrate cytokine production plasticity for human ILC2 and further suggest that environmental cues can dictate ILC phenotype and function for these tissue-resident innate effector cells.

Download Full-text