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1.
Science ; 384(6703): eadl0370, 2024 Jun 28.
Article in English | MEDLINE | ID: mdl-38935708

ABSTRACT

Innate lymphoid cells (ILCs) and adaptive T lymphocytes promote tissue homeostasis and protective immune responses. Their production depends on the transcription factor GATA3, which is further elevated specifically in ILC2s and T helper 2 cells to drive type-2 immunity during tissue repair, allergic disorders, and anti-helminth immunity. The control of this crucial up-regulation is poorly understood. Using CRISPR screens in ILCs we identified previously unappreciated myocyte-specific enhancer factor 2d (Mef2d)-mediated regulation of GATA3-dependent type-2 lymphocyte differentiation. Mef2d-deletion from ILC2s and/or T cells specifically protected against an allergen lung challenge. Mef2d repressed Regnase-1 endonuclease expression to enhance IL-33 receptor production and IL-33 signaling and acted downstream of calcium-mediated signaling to translocate NFAT1 to the nucleus to promote type-2 cytokine-mediated immunity.


Subject(s)
GATA3 Transcription Factor , Immunity, Innate , Interleukin-33 , MEF2 Transcription Factors , NFATC Transcription Factors , Pneumonia , Th2 Cells , Animals , Mice , MEF2 Transcription Factors/metabolism , MEF2 Transcription Factors/genetics , Th2 Cells/immunology , Interleukin-33/metabolism , NFATC Transcription Factors/metabolism , Pneumonia/immunology , GATA3 Transcription Factor/metabolism , GATA3 Transcription Factor/genetics , Mice, Inbred C57BL , Cell Differentiation , Calcium Signaling , Hypersensitivity/immunology , Lung/immunology , Allergens/immunology , Lymphocytes/immunology , Interleukin-1 Receptor-Like 1 Protein
2.
Immunity ; 56(7): 1468-1484.e7, 2023 07 11.
Article in English | MEDLINE | ID: mdl-37285842

ABSTRACT

Type 2 immune responses are critical in tissue homeostasis, anti-helminth immunity, and allergy. T helper 2 (Th2) cells produce interleukin-4 (IL-4), IL-5, and IL-13 from the type 2 gene cluster under regulation by transcription factors (TFs) including GATA3. To better understand transcriptional regulation of Th2 cell differentiation, we performed CRISPR-Cas9 screens targeting 1,131 TFs. We discovered that activity-dependent neuroprotector homeobox protein (ADNP) was indispensable for immune reactions to allergen. Mechanistically, ADNP performed a previously unappreciated role in gene activation, forming a critical bridge in the transition from pioneer TFs to chromatin remodeling by recruiting the helicase CHD4 and ATPase BRG1. Although GATA3 and AP-1 bound the type 2 cytokine locus in the absence of ADNP, they were unable to initiate histone acetylation or DNA accessibility, resulting in highly impaired type 2 cytokine expression. Our results demonstrate an important role for ADNP in promoting immune cell specialization.


Subject(s)
Histones , Transcription Factors , Histones/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Gene Expression Regulation , Th2 Cells , Cytokines/metabolism , Cell Differentiation , GATA3 Transcription Factor/genetics , GATA3 Transcription Factor/metabolism
3.
Nat Immunol ; 24(1): 123-135, 2023 01.
Article in English | MEDLINE | ID: mdl-36550322

ABSTRACT

Naive CD4+ T lymphocytes initially undergo antigen-specific activation to promote a broad-spectrum response before adopting bespoke cytokine expression profiles shaped by intercellular microenvironmental cues, resulting in pathogen-focused modular cytokine responses. Interleukin (IL)-4-induced Gata3 upregulation is important for the helper type 2 T cell (TH2 cell) polarization associated with anti-helminth immunity and misdirected allergic inflammation. Whether additional microenvironmental factors participate is unclear. Using whole mouse-genome CRISPR-Cas9 screens, we discovered a previously unappreciated role for αvß3 integrin in TH2 cell differentiation. Low-level αvß3 expression by naive CD4+ T cells contributed to pan-T cell activation by promoting T-T cell clustering and IL-2/CD25/STAT5 signaling. Subsequently, IL-4/Gata3-induced selective upregulation of αvß3 licensed intercellular αvß3-Thy1 interactions among TH2 cells, enhanced mammalian target of rapamycin (mTOR) signaling, supported differentiation and promoted IL-5/IL-13 production. In mice, αvß3 was required for efficient, allergen-driven, antigen-specific lung TH2 cell responses. Thus, αvß3-expressing TH2 cells form multicellular factories to propagate and amplify TH2 cell responses.


Subject(s)
Cytokines , Th2 Cells , Mice , Animals , Cytokines/metabolism , Cell Differentiation , Allergens , Lung , Mammals/metabolism
4.
Nat Immunol ; 22(2): 166-178, 2021 02.
Article in English | MEDLINE | ID: mdl-33432227

ABSTRACT

Type 2 innate lymphoid cells (ILC2) contribute to immune homeostasis, protective immunity and tissue repair. Here we demonstrate that functional ILC2 cells can arise in the embryonic thymus from shared T cell precursors, preceding the emergence of CD4+CD8+ (double-positive) T cells. Thymic ILC2 cells migrated to mucosal tissues, with colonization of the intestinal lamina propria. Expression of the transcription factor RORα repressed T cell development while promoting ILC2 development in the thymus. From RNA-seq, assay for transposase-accessible chromatin sequencing (ATAC-seq) and chromatin immunoprecipitation followed by sequencing (ChIP-seq) data, we propose a revised transcriptional circuit to explain the co-development of T cells and ILC2 cells from common progenitors in the thymus. When Notch signaling is present, BCL11B dampens Nfil3 and Id2 expression, permitting E protein-directed T cell commitment. However, concomitant expression of RORα overrides the repression of Nfil3 and Id2 repression, allowing ID2 to repress E proteins and promote ILC2 differentiation. Thus, we demonstrate that RORα expression represents a critical checkpoint at the bifurcation of the T cell and ILC2 lineages in the embryonic thymus.


Subject(s)
CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/metabolism , Cell Differentiation , Cell Lineage , Immunity, Innate , Nuclear Receptor Subfamily 1, Group F, Member 1/metabolism , Thymocytes/metabolism , Thymus Gland/metabolism , Animals , Basic-Leucine Zipper Transcription Factors/genetics , Basic-Leucine Zipper Transcription Factors/metabolism , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Cell Movement , Cells, Cultured , Coculture Techniques , Female , Gene Expression Regulation, Developmental , Inhibitor of Differentiation Protein 2/genetics , Inhibitor of Differentiation Protein 2/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Nuclear Receptor Subfamily 1, Group F, Member 1/genetics , Organ Culture Techniques , Phenotype , Repressor Proteins/genetics , Repressor Proteins/metabolism , Signal Transduction , Thymocytes/immunology , Thymus Gland/embryology , Thymus Gland/immunology , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolism
5.
J Mol Biol ; 428(19): 3869-84, 2016 09 25.
Article in English | MEDLINE | ID: mdl-27040396

ABSTRACT

CXCL8 (also known as interleukin-8 or IL-8) is a proinflammatory chemokine that not only modulates the inflammatory and immune responses, but whose upregulation is often associated with diseases including various types of cancer. Although numerous ligands for G protein-coupled receptors (GPCRs) have been shown to stimulate the production of CXCL8, the specificity of the G protein signal remains undefined. By expressing the constitutively active Gα subunits in HEK293 cells, CXCL8 production was herein demonstrated to be most effectively stimulated by Gαq family members, while those of Gαs and Gα12 elicited much weaker activities, and Gαi being totally ineffective. However, in cell lines such as HepG2, HeLa, and MCF-7 that endogenously express Gßγ-responsive phospholipase Cß isoforms (PLCß2/3), activation of the Gi-coupled α2-adrenoceptor significantly stimulated CXCL8 production. This Gi-induced CXCL8 production was apparently mediated via specific Gßγ dimers and required the presence of PLCß2/3. Co-activation of Gi-coupled α2-adrenoceptor and Gq-coupled bradykinin receptor resulted in a synergistic CXCL8 production, with Gßγ-responsive PLCß2/3, Src, ERK, and STAT3 serving as critical signaling intermediates. The treatment of HepG2 and B-10 endothelial cells with bradykinin stimulated CXCL8 production and cell proliferation. Interestingly, the latter response was driven by CXCL8 autocrine signaling because it was abolished by SB225002, an antagonist that prevents CXCL8 from binding to CXCR2. Collectively, our results provide a mechanistic basis for various G protein subfamilies to regulate the production of CXCL8, which may then lead to paracrine and/or autocrine signaling with major implications in both normal physiology and pathophysiological conditions.


Subject(s)
GTP-Binding Proteins/metabolism , Gene Expression Regulation , Interleukin-8/biosynthesis , Protein Subunits/metabolism , Receptors, Cell Surface/metabolism , Signal Transduction , Cell Line , Cell Proliferation , Humans
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