DUSP10 constrains innate IL-33-mediated cytokine production in ST2hi memory-type pathogenic Th2 cells
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ABSTRACT:
PROVIDER: PRJNA480393 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7503280.fastq.gz | Fastqsanger.gz | |||
| SRR7503281.fastq.gz | Fastqsanger.gz | |||
| SRR7503282.fastq.gz | Fastqsanger.gz |
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Project description:Memory CD4+ T helper (Th) cells are crucial for acquired immunity and protection from infectious microorganisms, and also drive pathogenesis of chronic inflammatory diseases, such as asthma. ST2hi memory-type Th2 cells have been identified as a pathogenic subpopulation capable of directly inducing eosinophilic airway inflammation. These ST2hi pathogenic Th2 cells produce large amounts of IL-5 upon stimulation via their TCR, but not in response to IL-33. In contrast, IL-33 alone induces cytokine production in ST2+ group 2 innate lymphoid cells (ILC2). We investigated the molecular mechanism that controls the innate function of IL-33-induced cytokine production, and identified a MAPK phosphatase Dusp10, as a key negative regulator of IL-33–induced cytokine production in Th2 cells. We found that Dusp10 is expressed by ST2hi pathogenic Th2 cells but not by ILC2, and Dusp10 expression inhibits IL-33-induced cytokine production by preventing GATA3 activity through inhibition of p38 MAPK phosphorylation. Strikingly, deletion of Dusp10 rendered ST2hi Th2 cells able to directly respond to IL-33 exposure and produce IL-5. Thus, DUSP10 constrains IL-33–induced cytokine production in ST2hi pathogenic Th2 cells by controlling p38-mediated GATA3 function.
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Project description:This study reveraled that androgen signaling suppresses differentiation and cytokine production of Th2 cells by inducing DUSP-2, explaining, in part, the sex bias of asthma after adolescence.
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Project description:The polarization of naïve CD4+ T cells into Th2 cells is initiated in lymphoid organs and completed as the cells become tissue resident, where they express ST2, the receptor for the alarmin IL-33, which may be a key signal for tissue integration. Cellular metabolic requirements associated with this transition remain poorly understood. To address this, we compared the response of lymphoid tissue (LT) Th2 cells from helminth parasite-infected mice to stimulation by IL-33 versus through the T cell receptor via anti-CD3/CD28. We found that IL-33, but not anti-CD3/CD28, induced the development of tissue-resident like Th2 cells expressing ST2. This was associated with IL-33 induced changes in arginine metabolism linked to mTORC1 activation and polyamine synthesis, which were required for the development of tissue-resident like Th2 cells. Furthermore, IL-33 induced transcriptional changes in genes involved in chemotaxis and cell adhesion that may be critical for tissue integration. Our findings provide insights into adaptations of Th2 cells responding to tissue-integration cues
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Project description:Androgens Alleviate Allergic Airway Inflammation by Suppressing Cytokine Production of Th2 Cells
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Project description:The differentiation of naïve CD4+ T cells into distinct effector T helper (Th) subsets is controlled by the chromatin state of the cells which in turn is regulated by various epigenetic mechanisms such as reversible lysine acetylation mediated by histone acetyltransferases and histone deacetylases (HDACs). In addition, Th2 cells can aquire pathogenic features, secreting pro-inflammatory factors and high levels of the cytokine IL-5. By using HDAC1 deficient naïve CD4+ T cells and establishing a protocol for differentiation of pathogenic Th2 cells, we could establish a critical role for HDAC1 in regulating the differentiation and pathogenicity of in vitro generated pathogenic Th2 cells
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Project description:Naive CD4+ T cells, sorted from PBMCs of grass-fed beef cattle, were stimulated with anti-bovine CD3 under Th2 differentiation conditions with or without Ostertagia ostertagi (OO) protein extract. Th1 differentiation conditions were included for comparison. The effect of recombinant bovine IL-4 (rbIL-4) and weakening TCR signal strength on Th2 differentiation were also tested. Flow cytometry, qPCR and proteomic assay were performed to analyze the differentiated cells.
The majority of differentiated cells expressed IFNgamma (a hallmark cytokine for Th1) and a small percentage of cells expressed both IFNgamma and IL-4 (a hallmark cytokine for Th2), indicating the presence of Th0 cells, as previously reported in cattle. While weakening TCR signal strength reduced Th2 cell expansion, adding rbIL-4 or OO protein extract enhanced Th2 cell expansion but without significant changes in IFNgamma and IL-4 expression. Proteomic data predicted that, as in mice and humans, bovine Th2 differentiation results from three upstream stimulation with CD3, CD28, and IL-4, which were inhibited when OO protein extract was added into the Th2 differentiation media. Importantly, protein profiling indicated that the addition of rbIL-4 enhanced IL-4 signaling but inhibited IL-12 signaling. Soon, we are planning to explore if other cytokines like IL-10 can be applied to optimize this Th2 differentiation in vitro.
Naive bovine CD4+ T cells differentiate into a mixed population containing a high percentage of IFNgamma producing cells and a small percentage of Th0 cells. Furthermore, bovine Th2 differentiation is sensitive to regulation such as by OO or rbIL-4.
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Project description:Allergic conjunctivitis is a chronic inflammatory disease that is characterized by severe itch in the conjunctiva; but how neuro-immune interactions shape the pathogenesis of severe itch remains unclear. We identified a subset of memory-type pathogenic Th2 cells that preferentially expressed Il1rl1-encoding ST2 and Calca-encoding calcitonin gene-related peptide (CGRP) in the inflammatory conjunctiva using a single-cell analysis. The IL-33-ST2 axis in memory Th2 cells controlled the axonal elongation of the peripheral sensory C-fiber and the induction of severe itch. Pharmacological blockade and genetic deletion of CGRP signaling in vivo attenuated scratching behavior. The analysis of giant papillae from patients with severe allergic conjunctivitis revealed ectopic lymphoid structure formation with the accumulation of IL-33-producing epithelial cells and CGRP-producing pathogenic CD4+ T cells accompanied by peripheral nerve elongation. Thus, the IL-33-ST2-CGRP axis directs severe itch with neuro-reconstruction in the inflammatory conjunctiva and is a potential therapeutic target for severe itch in allergic conjunctivitis.
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