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The transcription factor GATA3 is critical for the development of all IL-7Ra-expressing innate lymphoid cells (ILCs) and maintenance of type 2 ILCs

ABSTRACT: Innate lymphoid cells (ILCs) play critical roles during innate immune responses to pathogens and lymphoid organ development. IL-7Ra+ ILC subsets, similar to T helper (Th) cell subsets, produce distinctive effector cytokines. The molecular control of IL-7Ra+ ILC development and maintenance has yet to be dissected. Here we report that GATA3 is indispensable for the development of all IL-7Ra+ ILC subsets and T cells. Gata3 conditional deficient mice have no lymph nodes and are susceptible to Citrobactor rodentium infection. Genome-wide gene analyses indicate that GATA3 regulates similar set of cytokines and receptors in ILC2s and Th2 cells and is critical for the maintenance of ILC2s. Thus, GATA3 plays parallel roles in establishing and regulating both adaptive and innate lymphocytes.

ORGANISM(S): Mus musculus

PROVIDER: GSE47851 | GEO | 2014/03/13

SECONDARY ACCESSION(S): PRJNA208082

REPOSITORIES: GEO

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The transcription factor GATA3 is critical for the development of all IL-7Ra-expressing innate lymphoid cells (ILCs) and maintenance of type 2 ILCs

Project description:Innate lymphoid cells (ILCs) play critical roles during innate immune responses to pathogens and lymphoid organ development. IL-7Ra+ ILC subsets, similar to T helper (Th) cell subsets, produce distinctive effector cytokines. The molecular control of IL-7Ra+ ILC development and maintenance has yet to be dissected. Here we report that GATA3 is indispensable for the development of all IL-7Ra+ ILC subsets and T cells. Gata3 conditional deficient mice have no lymph nodes and are susceptible to Citrobactor rodentium infection. Genome-wide gene analyses indicate that GATA3 regulates similar set of cytokines and receptors in ILC2s and Th2 cells and is critical for the maintenance of ILC2s. Thus, GATA3 plays parallel roles in establishing and regulating both adaptive and innate lymphocytes. To identify GATA3 regulated genes in type 2 innate lymphoid cells by tamoxifen-mediated acute deletion of Gata3 gene.

2014-03-13 | E-GEOD-47851 | biostudies-arrayexpress

Transcriptional profiles of human circulating innate lymphoid cells and CD4 T helper cells

Project description:Innate lymphoid cells (ILCs) are part of the innate immune cell family. Three different subsets of ILCs, ILC1s, ILC2s and ILCPs can be identified in human peripheral blood. Based on their expression of transcription factors and cytokines, they are considered as being the innate counterparts of CD4 T helper subsets, namely Th1s, Th2s and Th17s. However, ILCs and Th cells have different roles in immunity. Therefore, we compared the transcriptomes of sorted ILC1s, ILC2s, ILCPs, Th1s, Th2s and Th17s from the peripheral blood of three different donors. RNA sequencing of ILC and Th subsets revealed differences in the expression of tens to hundreds of genes. These genes are involved in cell trafficking, innate activation and inhibitory functions. ILC and Th cell subsets also differ in their expressions of long-non coding RNAs.

2020-02-04 | E-MTAB-8494 | biostudies-arrayexpress

Group 3 innate lymphoid cells continuously require the transcription factor GATA3 after commitment

Project description:GATA3 is indispensable for the development of all IL-7RÎ±-expressing innate lymphoid cells (ILCs) and maintenance of type 1 ILCs (ILC1s) and type 2 ILCs (ILC2s). However, the importance of low GATA3 expression in type 3 ILCs (ILC3s) is still elusive. Here, we report that GATA3 regulates homeostasis of ILC3s by controlling IL-7RÎ± expression. In addition, GATA3 is critical for the development of NKp46+ ILC3 subset partially through regulating the balance between T-bet and RORÎ³t. Genome-wide analyses indicate that while GATA3 positively regulates CCR6+ and NKp46+ ILC3 subset-specific genes in respective lineages, it negatively regulates CCR6+ ILC3-specific genes in NKp46+ ILC3s. Furthermore, GATA3 regulates IL-22 production in both CCR6+ and NKp46+ ILC3s. Thus, low GATA3 expression is critical for the development and function of ILC3 subsets. To identify GATA3 regulated genes in total ILC3s with RNA-Seq; To identify unique genes expressed by CCR6+ ILC3 or NKp46+ ILC3 and GATA3 regulated genes within these two ILC3 subsets with RNA-Seq; To identify GATA3 direct binding sites in ILC3s, ILC2s and Th2 cells with ChIP-Seq.

2015-11-23 | E-GEOD-71198 | biostudies-arrayexpress

Unconventional ST2- and CD127-negative lung ILC2 populations are induced by Alternaria

Project description:Background: Alternaria exposure is associated with severe asthma in humans. Alternaria exposure in mice potently activates group 2 innate lymphoid cells (ILC2s) via the IL-33/ST2 axis and causes ILC2s to robustly secrete type 2 cytokines. Objective: Our aim was to determine whether conventionally used ILC2 markers, ST2 (IL-33R) and CD127 (IL-7Ra), were sufficient to identify all Th2-cytokine producing ILCs after Alternaria exposure. Methods: Mice received intranasal Alternaria for three days prior to analysis. Lung ILCs were identified by flow cytometry as CD45+Lineage−Thy1.2+ lymphocyte-sized cells, divided into four subsets based on ST2 and CD127 expression, and stained for intracellular cytokines and transcription factors. Sort-purified ILC subpopulations were also analyzed by RNA sequencing and qPCR. Results: Alternaria exposure led to accumulation of all ILC populations regardless of ST2 or CD127 expression. Nearly half of the GATA-3+, IL-5+, and IL-13+ ILCs were “unconventional” as they were either single or double negative for ST2/CD127. Further, these populations upregulated CD25, KLRG1, and ICOS after Alternaria challenge. Some activated unconventional IL-5+ ILC2s also produced IFNγ and IL-17A. In addition to shared ILC2 transcripts (Gata3, Il5, Il13) in all populations, RNA-seq further identified novel transcripts enriched in each subset. Finally, transcripts from all populations that correlated best with IL-5 and IL-13 production included Tnfrsf18, Ffar2, and Pde4b. Conclusions: Unconventional ST2- and CD127-negative mouse lung ILC2 populations are induced by Alternaria. Thus, commonly used lung ILC2 identification methods based on ST2 and CD127 do not accurately account for the total ILC2 burden and may exclude nearly half of these cells.

2019-08-22 | GSE136156 | GEO

Gene expression analysis of CD4+ and CD4- ILC1 subsets by RNAseq

Project description:Innate lymphoid cell (ILC) subsets that mirror helper T cells in their effector cytokine profiles have recently emerged as central players in both homeostatic and inflammatory conditions. Like their Th1, Th2 and Th17/Th22 helper T cell counterparts, ILC subsets are categorized based on their expression of specific transcription factors and effector cytokines: group 1 ILC (ILC1) express T-bet and IFN-Î³; group 2 ILC (ILC2) express GATA-3 and type 2 effector cytokines such as IL-13 and IL-5; and group 3 ILC (ILC3) express RORgt and the cytokines IL-22 and/or IL-17. Under this nomenclature, natural killer (NK) cells and lymphoid tissue inducers (LTi) are considered ILC1 and ILC3, respectively. ILC1 contain both CD4+ and CD4- populations, but whether this phenotypic characteristic reflects functional differences between these two populations is unknown. These studies examine the gene expression profiles of CD4+ vs CD4- ILC1 in a cohort of healthy control subjects. ILC subsets were isolated from the peripheral blood of healthy control subjects. cDNA was isolated and amplified from sorted populations, and gene expression was analyzed by RNAseq

2015-12-31 | E-GEOD-69596 | biostudies-arrayexpress

Proteome of group 2 innate lymphoid cells (ILC2s) stimulated with IL33 and TL1A

Project description:We analyzed the total proteome of group 2 innate lymphoid cells (ILC2s) after different stimulation with interleukin-33 (IL-33), a cytokine playing a critical role in human asthma, and TL1A, a TNF-family cytokine also known to activate ILC2s. Upon combined stimulation with IL-33 plus TL1A, we show that lung ILC2s produce high amounts of IL-9 and acquire a transient ‘ILC9’ phenotype. This phenotype is characterized by simultaneous production of large amounts of type 2 cytokines (IL-5, IL-13 and IL-9), induction of the IL-2 receptor CD25 (Il2ra), and of the transcription factors IRF4, JunB and BATF, that form immune-specific complexes known to induce IL-9 expression.

2024-03-05 | PXD041987 | Pride

RNA-binding protein RBM3 negatively regulates innate lymphoid cells (ILCs) and lung inflammation

Project description:Innate lymphoid cells (ILCs) promote lung inflammation in diseases such as asthma through cytokine production. RNA-binding proteins (RBPs) are critical post-transcriptional regulators of cellular function though the role of RBPs in innate lymphoid cells is unknown. Here, we demonstrate that RNA-binding motif 3 protein (RBM3) is one of the most highly expressed RBPs in Thy1.2+ lung ILCs after fungal allergen challenge and is further induced by epithelial cytokines TSLP and IL-33 in both human and mouse ILCs. Single (rbm3-/-) and double (rbm3-/-rag2-/-) knockout mice exposed via the airway to the asthma-associated fungal allergen Alternaria alternata displayed increases in eosinophilic lung inflammation and ILC activation compared to control mice. In addition to increased Th2 cytokine production, rbm3-/- ILCs produced elevated IL-17A. The negative regulation by RBM3 in ILC responses was direct as purified rbm3-/- ILCs were hyperinflammatory in vitro and in vivo after stimulation with IL-33. Transcriptomic analysis by RNA-sequencing of rbm3-/- lung ILCs showed increased type 2 and 17 cytokines as well as global expression differences in critical cytokines, receptors, transcription factors, and survival transcripts compared with WT ILCs. Importantly, these transcript changes were independent of the numbers of AU-rich elements (AREs) which RBM3 is known to bind. Thus, regulation of ILC responses by RNA-binding proteins offers novel mechanistic insight into lung ILC biology and ILC-driven inflammatory diseases.

2021-01-01 | GSE155330 | GEO

Gene expression analysis of CD4+ and CD4- ILC1 subsets by RNAseq

Project description:Innate lymphoid cell (ILC) subsets that mirror helper T cells in their effector cytokine profiles have recently emerged as central players in both homeostatic and inflammatory conditions. Like their Th1, Th2 and Th17/Th22 helper T cell counterparts, ILC subsets are categorized based on their expression of specific transcription factors and effector cytokines: group 1 ILC (ILC1) express T-bet and IFN-γ; group 2 ILC (ILC2) express GATA-3 and type 2 effector cytokines such as IL-13 and IL-5; and group 3 ILC (ILC3) express RORgt and the cytokines IL-22 and/or IL-17. Under this nomenclature, natural killer (NK) cells and lymphoid tissue inducers (LTi) are considered ILC1 and ILC3, respectively. ILC1 contain both CD4+ and CD4- populations, but whether this phenotypic characteristic reflects functional differences between these two populations is unknown. These studies examine the gene expression profiles of CD4+ vs CD4- ILC1 in a cohort of healthy control subjects.

2015-12-31 | GSE69596 | GEO

Tissue signals imprint ILC2 identity with anticipatory function [single cell RNA-Seq]

Project description:Group 2 innate lymphoid cells (ILC2s) are distributed systemically and produce type 2 cytokines in response to a variety of stimuli, including the epithelial cytokines interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP). Transcriptional profiling of ILC2s from different tissues, however, grouped ILC2s according to their tissue of origin, even in the setting of combined IL-25, IL-33R and TSLPR-deficiency. Single-cell profiling confirmed a tissue-organizing transcriptome and identified ILC2 subsets expressing distinct activating receptors, including the major subset of skin ILC2s, which were activated preferentially by IL-18. Tissue ILC2 subsets were normal in germ- free mice, suggesting that endogenous, tissue-derived, signals drive the maturation of ILC2 subsets by controlling expression of distinct patterns of activating receptors, thus anticipating tissue-specific patterns to perturbations occurring later in life.

2018-09-10 | GSE117567 | GEO

Tissue signals imprint ILC2 identity with anticipatory function [RNA-Seq]

2018-09-10 | GSE117470 | GEO

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