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Down-regulation of E protein activity augments an ILC2 differentiation program in the thymus

ABSTRACT: Innate lymphoid cells (ILCs) are important regulators in various immune responses. Current paradigm states that all newly-made ILCs originate from common lymphoid progenitors (CLP) in the bone marrow. Id2, an inhibitor of E protein transcription factors, is indispensable for ILC differentiation. Unexpectedly, we found that ectopically expressing Id1 or deleting two E protein genes in the thymus drastically increased ILC2 counts in the thymus and other organs where ILC2 normally reside. Further evidence suggests a thymic origin of these mutant ILC2s. The mutant mice exhibit augmented spontaneous infiltration of eosinophils and heightened responses to papain in the lung and increased ability to expulse the helminth parasite, Nippostrongylus brasiliensis. These results prompt the question whether the thymus naturally has the capacity to produce ILC2s and E proteins restrain such a potential. The abundance of ILC2s in Id1 transgenic mice also offers a unique opportunity for testing the biological functions of ILC2s.

ORGANISM(S): Mus musculus

PROVIDER: GSE94597 | GEO | 2017/02/08

SECONDARY ACCESSION(S): PRJNA371571

REPOSITORIES: GEO

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Transcription factor Bcl11b controls identity and function of mature innate lymphoid cells type II

Project description:Type-2 innate lymphoid cells (ILC2s) promote anti-helminth responses and contribute to allergies. Though Bcl11b has been previously considered a T-lineage identity transcription factor (TF) that restrains the innate-cell genetic programs, we report here that Bcl11b is highly expressed in mature ILC2s and acts upstream of the key ILC2 TFs Gfi1, Gata-3, and of IL-33 receptor IL1rl1 (T1ST2). Additionally, Bcl11b-/- ILC2s de-repressed Rorγt, Ahr and IL-23 receptor, normally expressed in type-3 ILCs (ILC3s). Consequently, Bcl11b-/- ILC2s lost ILC2 functions and gained ILC3 functions, expanding in response to the protease allergen papain, however producing IL-17 and IL-22, and not IL-5 and IL-13, causing lung neutrophilia rather than eosinophilia, and diminished mucus production. Our results broaden Bcl11b's role from a T-cell only TF, and establishes that Bcl11b sustains mature ILC2 genetic and functional programs and lineage fidelity through positive regulation of essential ILC2 TFs and negative regulation of pivotal ILC3 TFs. RNA-seq analysis on sorted ILC2s from the mLNs of Bcl11bF/F Cre-ERT2 and wildtype mice at steady state following tamoxifen mediated deletion of Bcl11b

2015-07-28 | E-GEOD-67437 | biostudies-arrayexpress

E-protein inhibition in ILC2 development shapes the function of mature ILC2s during allergic airway inflammation

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2021-10-18 | GSE185950 | GEO

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2021-03-05 | GSE164705 | GEO

Specification of innate type-2 lymphocytes by the transcriptional determinant Gfi1

Project description:Innate type-2 lymphoid cells (ILC2s) function in immune responses against helminth parasites and are implicated in allergic inflammation and asthma. ILC2s are activated by the epithelial-derived cytokines IL-33 and IL-25 and are major sources of the type-2 cytokines IL-5 and IL-13. We show that the transcription factor Gfi1 promotes the generation of ILC2s and controls their responsiveness during Nippostrongylus brasiliensis infection as well as IL-33- or IL-25-instigated inflammation. Gfi1 directly activates Il1rl1, which encodes the IL-33 receptor. IL- 33 signaling upregulates Gfi1, thereby constituting a positive feedback loop that enables rapid and robust expansion of ILC2s in response to IL-33 signaling. Loss of Gfi1 in activated ILC2s results in an unusual effector state involving derepression of the IL-17 inflammatory program and co-expression of IL-13 with IL-17. ChIPseq reveals key Gfi1 targeted genes that are activated or repressed to maintain ILC2 identity. We propose that Gfi1 functions as a shared determinant within innate and adaptive immune cells to specify type-2 responses, while actively repressing the IL-17 effector state. ILC2s (~3 x 10^7 cells) were sorted from the MLN of IL-25-treated mice. Chromatin fragments bound by Gfi1 were subject to ChIP using Gfi1 antibodies and followed by high-throughput sequencing.

2013-09-13 | E-GEOD-50806 | biostudies-arrayexpress

Transcription factor Bcl11b controls identity and function of mature innate lymphoid cells type II

2015-07-28 | GSE67437 | GEO

The neuropeptide Neuromedin U stimulates innate lymphoid cells and promotes type 2 inflammation [ILC2 and ILC3]

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2017-08-18 | GSE101623 | GEO

Analysis of R5-/+ and Mc5rfl/fl R5-/+ lung ILC2 transcriptomes in papain induced acute lung inflammation

Project description:melanocortin 5 receptor (Mc5r) have various effects in immune responses. However, the involvement of Mc5r in ILC2 functions remains unclear. We identified the genes regulated by Mc5r in lung ILC2s during papain induced acute lung inflammation.

2023-08-08 | GSE237962 | GEO

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

Comprehensive protein-expression map of ILC2 and ILC3 subsets in healthy human skin

Project description:Innate lymphoid cells (ILCs) have emerged as essential players in the skin-associated immune system in health and inflammatory skin diseases. Their low numbers and lack of specific markers hampered extensive characterization and consequently resulted in limited knowledge of their protein expression. Here, we combined flow cytometry and state-of-the-art proteomics to comprehensively describe the proteins constitutively expressed by ILC2 and ILC3 subsets derived from healthy human skin and peripheral blood. We quantified 6666 proteins from skin ILC and identified 608 differentially expressed proteins in the investigated subsets. In addition to the current analyses, highlighting new functions of ILC, the ILC proteomic libraries and the proteomes of the ILC2 and ILC3 subsets will serve as valuable resources for future analyses of ILC function and are available at http://skin.science.

2023-10-10 | PXD037817 | Pride

RNA-seq analysis of the Innate Lymphoid Cells type 2 (ILC2) or their precursors (ILC2p ) sorted from WT and Tgfbr2-/- mice

Project description:Purpose: The molecular pathways underlying the development of innate lymphoid cells (ILCs) are mostly unknown. Results: TGF-β signaling programs the development of ILC2s from their progenitors. Specifically, the deficiency of TGF-β receptor II in bone marrow progenitors results in inefficient development of ILC2s, but not ILC1s or ILC3s. We found that hundreds of genes were changed in Tgfbr2-/- ILC2s compared to WT ILC2s (FDR < 0.1 and Fold-Change >1.5). Some ILC2-associated genes including Gata3, Il1rl1 (ST2), Il-5, Atxn1 (Sca1), and Ccr4 were decreased in Tgfbr2-/- ILC2s, according to RNA-seq analysis Conclusions: TGF-β upregulates the expression of the IL-33 receptor gene Il1rl1 (encoding IL-1 receptor-like 1, also known as ST2) in ILC2p and common helper-like innate lymphoid progenitors (CHILP), at least partially through the MEK-dependent pathway. These findings identify a function of TGF-β in the development of ILC2s from their progenitors.

2019-11-09 | GSE140168 | GEO

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