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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE67437 | GEO | 2015/07/28

SECONDARY ACCESSION(S): PRJNA279899

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

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Project description:This SuperSeries is composed of the SubSeries listed below. Group 2 innate lymphoid cells (ILC2) are a subset of innate lymphocytes that produce type 2 cytokines, including IL-4, IL-5, and IL-13. GATA3 being a critical transcription factor for ILC2 development at multiple stages. However, when and how GATA3 is induced to the levels required for ILC2 development remains elusive. Herein, we identified ILC2-specific tandem GATA3-related super-enhancers (G3SE) that induce high GATA3 in ILC2-committed precursors. G3SE-deficient mice exhibit ILC2 loss in the BM, lung, liver, and small intestine, a slight ILC1 increase, and no difference in ILC3, LTi, NK cells, nor Th2 cells. Single-cell RNA-sequencing revealed that GATA3 induction in late ILC2-committed precursors depends on G3SEs and is required for the transition to mature ILC2. Cnot6l, part of the CCR4-Not deadenylase complex, is a possible GATA3 target during ILC2 development. Our findings indicate a novel regulatory mechanism for GATA3 expression during ILC2 development.

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Bulk RNA sequencing of WT and Batf-/- ILC2s sorted from lungs at day 9 after influenza virus infection

Project description:Activated type 2 innate lymphoid cells (ILC2s) accumulate and promote inflammatory resolution and tissue repair in host defense against acute respiratory viral infections. However, whether an ILC2 subset that specializes in wound healing exists, and the mechanisms by which ILC2 cells contribute to tissue repair remain elusive. Using single-cell RNA-sequencing (scRNA-seq), we identified a transcriptionally distinct ILC2 subset that showed enrichment for wound healing signature genes and the transcription factor BATF. Notably, BATF promoted the proliferation and function of ILC2s and restricted their plasticity during infection with influenza virus. In the absence of BATF, ILC2s lost their immune protective properties and obtained pathogenic ILC3-like function, which led to persist neutrophil infiltration, tissue damage and lethality. Mechanistically, BATF directly bound the cis-regulatory elements of wound healing genes, maintained their chromatin accessibility and promoted their expression. Lastly, BATF played an important role in an IL-33-ST2 feed-forward loop that supports ILC2 cell identity and function. Collectively, our findings shed light on a BATF-dependent ILC2 program thereby providing a potential therapeutic target for terminating detrimental inflammation during acute viral infection.

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