scholarly journals The skin environment controls local dendritic cell differentiation and function through innate IL-13

2021 ◽  
Author(s):  
Johannes U Mayer ◽  
Olivier Lamiable ◽  
Kerry L Hilligan ◽  
Jodie S Chandler ◽  
Samuel I Old ◽  
...  
Keyword(s):  
Gene Signature ◽  
Lymphoid Cells ◽  
Healthy Skin ◽  
Developmental Pathway ◽  
Dendritic Cell Differentiation ◽  
Phenotype Analysis ◽  
Public Datasets ◽  
And Function ◽  
Anti Fungal

ABSTRACTThe signals driving the adaptation of type-2 dendritic cells (DC2s) to diverse peripheral environments are not well understood. We show that the development of CD11blow migratory DC2s, a DC2 population unique to the dermis, requires STAT6- and KLF4-dependent IL-13 signaling, whereas DC2s in lung and small intestine are STAT6-independent. Dermal IL-13 is mostly derived from innate lymphoid cells expressing a resting ICOS+ KLRG1-ST2-phenotype. Analysis of public datasets indicates that human skin DC2s also express an IL-4/IL-13 gene signature compared to blood or spleen, suggesting a similar developmental pathway in mice and humans. In the absence of IL-13 signaling, dermal DC2s are stable in number but remain CD11bhi and show defective activation in response to allergen with diminished ability to support IL-4+ GATA3+ Th development, whereas anti-fungal IL-17+ RORγt+ responses are increased. Thus, steady-state IL-13 fosters a non-inflammatory and pro-allergic environment in healthy skin via conditioning of local DC2s.

Regulating the development of pulmonary Group 2 innate lymphoid cells

2019 ◽  
Vol 400 (11) ◽  
pp. 1497-1507 ◽  
Author(s):  
Sofia Helfrich ◽  
Claudia U. Duerr
Keyword(s):  
Transcription Factors ◽  
Immune Responses ◽  
Morphological Changes ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
The Family ◽  
Intrinsic Regulation ◽  
Group 2 ◽  
And Function

Abstract Group 2 innate lymphoid cells (ILC2s) are members of the family of innate lymphoid cells and are innately committed to type 2 immune responses. In the lungs, ILC2s are the predominant population of innate lymphoid cells (ILCs) and their development is orchestrated by several different transcription factors ensuring lineage commitment by intrinsic regulation. ILC2s are present in the lungs from the foetal period onwards and are thus exposed to extrinsic regulation due to the airways’ continuous morphological changes upon birth. In this review, we will briefly summarise the dependence of ILC2s on transcription factors and discuss recently described characteristics and function of early life ILC2s in the lungs.

scholarly journals Transcription Factor Bcl11b Controls Identity and Function of Mature Type 2 Innate Lymphoid Cells

Immunity ◽  
2015 ◽  
Vol 43 (2) ◽  
pp. 354-368 ◽  
Author(s):  
Danielle Califano ◽  
Jonathan J. Cho ◽  
Mohammad N. Uddin ◽  
Kyle J. Lorentsen ◽  
Qi Yang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Mature Type ◽  
And Function

scholarly journals RORα-dependent type 2 innate lymphoid cells are required and sufficient for mucous metaplasia in immature mice

2017 ◽  
Vol 312 (6) ◽  
pp. L983-L993 ◽  
Author(s):  
Charu Rajput ◽  
Tracy Cui ◽  
Mingyuan Han ◽  
Jing Lei ◽  
Joanna L. Hinde ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Retinoic Acid Receptor ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Orphan Receptor ◽  
Adult Mice ◽  
Mucous Metaplasia ◽  
And Function ◽  
Cluster Of Differentiation

Early-life wheezing-associated respiratory tract infection by rhinovirus (RV) is considered a risk factor for asthma development. We have shown that RV infection of 6-day-old BALB/c mice, but not mature mice, induces an asthmalike phenotype that is associated with an increase in the population of type 2 innate lymphoid cells (ILC2s) and dependent on IL-13 and IL-25. We hypothesize that ILC2s are required and sufficient for development of the asthmalike phenotype in immature mice. Mice were infected with RV1B on day 6 of life and treated with vehicle or a chemical inhibitor of retinoic acid receptor-related orphan receptor-α (RORα), SR3335 (15 mg·kg−1·day−1ip for 7 days). We also infected Rorasg/sgmice without functional ILC2s. ILC2s were identified as negative for lineage markers and positive for cluster of differentiation 25 (CD25)/IL-2Rα and CD127/IL-7Rα. Effects of SR3335 on proliferation and function of cultured ILC2s were determined. Finally, sorted ILC2s were transferred into naïve mice, and lungs were harvested 14 days later for assessment of gene expression and histology. SR3335 decreased the number of RV-induced lung lineage-negative, CD25+, CD127+ILC2s in immature mice. SR3335 also attenuated lung mRNA expression of IL-13, Muc5ac, and Gob5 as well as mucous metaplasia. We also found reduced expansion of ILC2s in RV-infected Rorasg/sgmice. SR3335 also blocked IL-25 and IL-33-induced ILC2 proliferation and IL-13 production ex vivo. Finally, adoptive transfer of ILC2s led to development of asthmalike phenotype in immature and adult mice. RORα-dependent ILC2s are required and sufficient for type 2 cytokine expression and mucous metaplasia in immature mice.

scholarly journals A Gata3 enhancer necessary for ILC2 development and function

2021 ◽  
Vol 118 (32) ◽  
pp. e2106311118
Author(s):  
Darshan N. Kasal ◽  
Zhitao Liang ◽  
Maile K. Hollinger ◽  
Crystal Y. O’Leary ◽  
Wioletta Lisicka ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Lymphoid Cells ◽  
Th2 Cells ◽  
Regulatory Pathways ◽  
Th2 Cell ◽  
Gata3 Expression ◽  
Gene Regulatory ◽  
High Level ◽  
And Function

The type 2 helper effector program is driven by the master transcription factor GATA3 and can be expressed by subsets of both innate lymphoid cells (ILCs) and adaptive CD4+ T helper (Th) cells. While ILC2s and Th2 cells acquire their type 2 differentiation program under very different contexts, the distinct regulatory mechanisms governing this common program are only partially understood. Here we show that the differentiation of ILC2s, and their concomitant high level of GATA3 expression, are controlled by a Gata3 enhancer, Gata3 +674/762, that plays only a minimal role in Th2 cell differentiation. Mice lacking this enhancer exhibited defects in several but not all type 2 inflammatory responses, depending on the respective degree of ILC2 and Th2 cell involvement. Our study provides molecular insights into the different gene regulatory pathways leading to the acquisition of the GATA3-driven type 2 helper effector program in innate and adaptive lymphocytes.

scholarly journals Single-cell transcriptional analysis reveals naïve helper ILC-like cells in zebrafish

2018 ◽  
Author(s):  
Pedro P. Hernández ◽  
Paulina M. Strzelecka ◽  
Emmanouil I. Athanasiadis ◽  
Ana F. Robalo ◽  
Catherine M. Collins ◽  
...  
Keyword(s):  
Single Cell ◽  
Lymphoid Cells ◽  
Transcriptional Analysis ◽  
Environmental Cues ◽  
Immune Challenge ◽  
Wild Type ◽  
And Function ◽  
Type 3 ◽  
Barrier Tissues

AbstractInnate lymphoid cells (ILCs) are important mediators of the immune response and homeostasis in barrier tissues of mammals. However, the existence and function of ILCs in other vertebrates is poorly understood. Here, we use single-cell RNA sequencing to generate a comprehensive atlas of zebrafish lymphocytes during tissue homeostasis and following immune challenge. We profiled 14,080 individual cells from the gut of wild-type zebrafish, as well as of rag1-deficient fish which lack T and B cells, and discovered diverse populations of helper ILC-like cells. Unexpectedly, fish displayed a rorc-positive, naïve subset that established a Type 3 or Type 2 response only upon immune challenge. Specifically, naïve ILC-like cells expressed il22 and tnfa following exposure to inactivated bacteria, or il13 following exposure to helminth extract. Cytokine-producing ILC-like cells express a specific repertoire of novel immune-type receptors, likely involved in recognition of environmental cues. We identified additional novel markers of zebrafish ILCs and generated a cloud repository for their in-depth exploration.

scholarly journals Dichotomous metabolic networks govern human ILC2 proliferation and function

2021 ◽  
Author(s):  
Laura Surace ◽  
Jean-Marc Doisne ◽  
Carys A. Croft ◽  
Anna Thaller ◽  
Pedro Escoll ◽  
...  
Keyword(s):  
Amino Acids ◽  
Metabolic Networks ◽  
Mammalian Target Of Rapamycin ◽  
Immune Defense ◽  
Lymphoid Cells ◽  
Interleukin 33 ◽  
Type 2 Cytokines ◽  
Group 2 ◽  
And Function

AbstractGroup 2 innate lymphoid cells (ILC2s) represent innate homologs of type 2 helper T cells (TH2) that participate in immune defense and tissue homeostasis through production of type 2 cytokines. While T lymphocytes metabolically adapt to microenvironmental changes, knowledge of human ILC2 metabolism is limited, and its key regulators are unknown. Here, we show that circulating ‘naive’ ILC2s have an unexpected metabolic profile with a higher level of oxidative phosphorylation (OXPHOS) than natural killer (NK) cells. Accordingly, ILC2s are severely reduced in individuals with mitochondrial disease (MD) and impaired OXPHOS. Metabolomic and nutrient receptor analysis revealed ILC2 uptake of amino acids to sustain OXPHOS at steady state. Following activation with interleukin-33 (IL-33), ILC2s became highly proliferative, relying on glycolysis and mammalian target of rapamycin (mTOR) to produce IL-13 while continuing to fuel OXPHOS with amino acids to maintain cellular fitness and proliferation. Our results suggest that proliferation and function are metabolically uncoupled in human ILC2s, offering new strategies to target ILC2s in disease settings.

scholarly journals ICAM-1 controls development and function of ILC2

2018 ◽  
Vol 215 (8) ◽  
pp. 2157-2174 ◽  
Author(s):  
Ai-Hua Lei ◽  
Qiang Xiao ◽  
Gao-Yu Liu ◽  
Kun Shi ◽  
Qiong Yang ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Allergic Airway Inflammation ◽  
Lymphoid Cells ◽  
Peripheral Tissues ◽  
Type 2 Cytokines ◽  
Functionally Impaired ◽  
Group 2 ◽  
And Function

Group 2 innate lymphoid cells (ILC2s) are emerging as key players in the pathogenesis of allergic airway inflammation. The mechanisms regulating ILC2, however, are not fully understood. Here, we found that ICAM-1 is required for the development and function of ILC2. ICAM-1–deficient (ICAM-1−/−) mice displayed significantly lower levels of ILC2s in the bone marrow and peripheral tissues than wild-type controls. CLP transfer and in vitro culture assays revealed that the regulation of ILC2 by ICAM-1 is cell intrinsic. Furthermore, ILC2s from ICAM-1−/− mice were functionally impaired, as indicated by the diminished production of type-2 cytokines in response to IL-33 challenge. The reduction in lung ILC2s caused a clear remission of airway inflammation in ICAM-1−/− mice after administration of papain or Alternaria alternata. We further demonstrate that ILC2 defects caused by ICAM-1 deficiency are due to ERK signaling-dependent down-regulation of GATA3 protein. Collectively, these observations identify ICAM-1 as a novel regulator of ILC2.

scholarly journals MicroRNA regulation of type 2 innate lymphoid cell homeostasis and function in allergic inflammation

2017 ◽  
Vol 214 (12) ◽  
pp. 3627-3643 ◽  
Author(s):  
Priti B. Singh ◽  
Heather H. Pua ◽  
Hannah C. Happ ◽  
Christoph Schneider ◽  
Jakob von Moltke ◽  
...  
Keyword(s):  
Target Genes ◽  
Therapeutic Potential ◽  
Allergic Inflammation ◽  
Lymphoid Cells ◽  
Th2 Cells ◽  
Signaling Inhibitors ◽  
Regulated Gene Expression ◽  
And Function

MicroRNAs (miRNAs) exert powerful effects on immunity through coordinate regulation of multiple target genes in a wide variety of cells. Type 2 innate lymphoid cells (ILC2s) are tissue sentinel mediators of allergic inflammation. We established the physiological requirements for miRNAs in ILC2 homeostasis and immune function and compared the global miRNA repertoire of resting and activated ILC2s and T helper type 2 (TH2) cells. After exposure to the natural allergen papain, mice selectively lacking the miR-17∼92 cluster in ILC2s displayed reduced lung inflammation. Moreover, miR-17∼92–deficient ILC2s exhibited defective growth and cytokine expression in response to IL-33 and thymic stromal lymphopoietin in vitro. The miR-17∼92 cluster member miR-19a promoted IL-13 and IL-5 production and inhibited expression of several targets, including SOCS1 and A20, signaling inhibitors that limit IL-13 and IL-5 production. These findings establish miRNAs as important regulators of ILC2 biology, reveal overlapping but nonidentical miRNA-regulated gene expression networks in ILC2s and TH2 cells, and reinforce the therapeutic potential of targeting miR-19 to alleviate pathogenic allergic responses.

scholarly journals Subset- and tissue-defined STAT5 thresholds control homeostasis and function of innate lymphoid cells

2017 ◽  
Vol 214 (10) ◽  
pp. 2999-3014 ◽  
Author(s):  
Alejandro V. Villarino ◽  
Giuseppe Sciumè ◽  
Fred P. Davis ◽  
Shigeru Iwata ◽  
Beatrice Zitti ◽  
...  
Keyword(s):  
Nk Cells ◽  
Gene Signature ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Barrier Integrity ◽  
Central Node ◽  
Genome Wide ◽  
Genetic Tuning ◽  
And Function ◽  
Environmental Interfaces

Innate lymphoid cells (ILCs) patrol environmental interfaces to defend against infection and protect barrier integrity. Using a genetic tuning model, we demonstrate that the signal-dependent transcription factor (TF) STAT5 is critical for accumulation of all known ILC subsets in mice and reveal a hierarchy of STAT5 dependency for populating lymphoid and nonlymphoid tissues. We apply transcriptome and genomic distribution analyses to define a STAT5 gene signature in natural killer (NK) cells, the prototypical ILC subset, and provide a systems-based molecular rationale for its key functions downstream of IL-15. We also uncover surprising features of STAT5 behavior, most notably the wholesale redistribution that occurs when NK cells shift from tonic signaling to acute cytokine-driven signaling, and genome-wide coordination with T-bet, another key TF in ILC biology. Collectively, our data position STAT5 as a central node in the TF network that instructs ILC development, homeostasis, and function and provide mechanistic insights on how it works at cellular and molecular levels.

A pro-inflammatory role of type 2 innate lymphoid cells in murine immune-mediated hepatitis

2015 ◽  
Vol 53 (12) ◽  
Author(s):  
K Karimi ◽  
K Neumann ◽  
J Meiners ◽  
R Voetlause ◽  
W Dammermann ◽  
...  
Keyword(s):  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Immune Mediated
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