IL-4/IL-13 Signaling Inhibits the Potential of Early Thymic Progenitors To Commit to the T Cell Lineage

Barik, Subhasis; Miller, Mindy M.; Cattin-Roy, Alexis N.; Ukah, Tobechukwu K.; Chen, Weirong; Zaghouani, Habib

doi:10.4049/jimmunol.1700498

Cited by 18 publications

(26 citation statements)

References 42 publications

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“…39) IL-4 is one of the main Th2-producing cytokines that plays a crucial role in inflammatory events and promotes differentiation and proliferation of Th2 cells. 40) Recent studies have indicated that IL-4 in the thymus inhibits the commitment of early thymic progenitor cells to T cell lineage as well as the differentiation of CD8 + cytotoxic T cells. 41,42) IL-4 expression in the thymus may be strictly controlled to avoid its unpleasant effect on T cell development.…”

Section: Diet-restriction-induced Thymic Involution Involves the Polamentioning

confidence: 99%

Induced Prostanoid Synthesis Regulates the Balance between Th1- and Th2-Producing Inflammatory Cytokines in the Thymus of Diet-Restricted Mice

Razali

Hitomi

Inazumi

et al. 2020

Biological & Pharmaceutical Bulletin

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Multiple external and internal factors have been reported to induce thymic involution. Involution involves dramatic reduction in size and function of the thymus, leading to various immunodeficiency-related disorders. Therefore, clarifying and manipulating molecular mechanisms governing thymic involution are clinically important, although only a few studies have dealt with this issue. In the present study, we investigated the molecular mechanisms underlying thymic involution using a murine acute diet-restriction model. Gene expression analyses indicated that the expression of T helper 1 (Th1)-producing cytokines, namely interferon-γ and interleukin (IL)-2, was down-regulated, while that of Th2-producing IL-5, IL-6, IL-10 and IL-13 was up-regulated, suggesting that acute diet-restriction regulates the polarization of naïve T cells to a Th2-like phenotype during thymic involution. mRNAs for prostanoid biosynthetic enzymes were up-regulated by acute diet-restriction. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyses detected the increased production of prostanoids, particularly prostaglandin D 2 and thromboxane B 2 , a metabolite of thromboxane A 2 , in the diet-restricted thymus. Administration of non-steroidal anti-inflammatory drugs, namely aspirin and etodolac, to inhibit prostanoid synthesis suppressed the biased expression of Th1and Th2-cytokines as well as molecular markers of Th1 and Th2 cells in the diet-restricted thymus, without affecting the reduction of thymus size. In vitro stimulation of thymocytes with phorbol myristate acetate (PMA)/ionomycin confirmed the polarization of thymocytes from diet-restricted mice toward Th2 cells. These results indicated that the induced production of prostanoids during diet-restriction-induced thymic involution is involved in the polarization of naïve T cells in the thymus.

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Section: Diet-restriction-induced Thymic Involution Involves the Polamentioning

confidence: 99%

Induced Prostanoid Synthesis Regulates the Balance between Th1- and Th2-Producing Inflammatory Cytokines in the Thymus of Diet-Restricted Mice

Razali

Hitomi

Inazumi

et al. 2020

Biological & Pharmaceutical Bulletin

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“…These CD8 “memory-like” T cells have important roles in early defenses, particularly in situations of chronic viral infection 6 , 7 . Thymic steady-state IL-4 also drives the acquisition of an activated/memory-like phenotype by Foxp3 + regulatory T cells 8 , the production of chemokines by thymic dendritic cells 2 , the thymic exit of mature “conventional” T cells 9 and also perhaps the commitment of early thymic progenitors to the T cell lineage 10 . Additionally, RANKL-expressing CD44 − thymic iNKT cells (which are preferentially enriched for iNKT2 and iNKT17 cells) regulate the differentiation of Aire + MHC class II + medullary thymic epithelial cells 11 that are involved in clonal deletion of self-reactive T cells 12 and Treg maturation 13 .…”

Section: Introductionmentioning

confidence: 99%

TCR signal strength controls thymic differentiation of iNKT cell subsets

et al. 2018

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During development in the thymus, invariant natural killer T (iNKT) cells commit to one of three major functionally different subsets, iNKT1, iNKT2, and iNKT17. Here, we show that T cell antigen receptor (TCR) signal strength governs the development of iNKT cell subsets, with strong signaling promoting iNKT2 and iNKT17 development. Altering TCR diversity or signaling diminishes iNKT2 and iNKT17 cell subset development in a cell-intrinsic manner. Decreased TCR signaling affects the persistence of Egr2 expression and the upregulation of PLZF. By genome-wide comparison of chromatin accessibility, we identify a subset of iNKT2-specific regulatory elements containing NFAT and Egr binding motifs that is less accessible in iNKT2 cells that develop from reduced TCR signaling. These data suggest that variable TCR signaling modulates regulatory element activity at NFAT and Egr binding sites exerting a determinative influence on the dynamics of gene enhancer accessibility and the developmental fate of iNKT cells.

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“…We took advantage of KEGG analyses to point out that hsa_circ_0005519 could be related to the MAPK and JAK‐STAT signalling pathways in asthma. IL‐6 and IL‐13, which are important inflammatory mediators in asthma as mentioned above, play a role in T cell differentiation and activation by MAPK or JAK‐STAT signalling pathways . And accumulating evidence indicates that these two signalling pathways are involved in regulating cytokines such as IL‐6 and IL‐13 in asthma inflammation .…”

Section: Discussionmentioning

confidence: 97%

Hsa_circ_0005519 increases IL‐13/IL‐6 by regulating hsa‐let‐7a‐5p in CD4⁺ T cells to affect asthma

Huang

Cao

Zhou

et al. 2019

Clin Experimental Allergy

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Background: Circular RNAs (circRNAs) are a class of non-coding RNAs that could serve as novel biomarkers for the diagnosis and treatment of diseases. We hypothesized that circRNAs of CD4 + T cells are involved in asthma. Objective:In this study, we investigated the circRNA expression profile and the possible mechanism by which hsa_circ_0005519 participates in asthma. Methods:The expression profiles of circRNAs in CD4 + T cells were revealed by circRNA microarray. Hsa_circ_0005519 expression in CD4 + T cells was confirmed in asthmatic patients (n = 65) and healthy subjects (n = 30). Hsa-let-7a-5p, the target of hsa_circ_0005519, was predicted by online algorithms and verified by a dual-luciferase reporter assay. Correlation assays between the expression of hsa_ circ_0005519 and hsa-let-7a-5p, the mRNA levels of interleukin (IL)-13 and IL-6 in CD4 + T cells, and the clinical characteristics of asthmatic patients were performed.The role of hsa_circ_0005519 in proinflammatory cytokine expression was investigated in CD4 + T cells from asthmatic patients in vitro. Hsa_circ_0005519 expression in PBMCs was determined in another cohort including 30 asthmatic patients and 24 controls. Correlation assays of hsa_circ_0005519 expressions between CD4 + T cells and PBMCs were performed.Results: Hsa_circ_0005519 was up-regulated and negatively correlated with hsalet-7a-5p expression in CD4 + T cells of asthmatic patients. Both the fraction of exhaled nitric oxide (FeNO) and the peripheral blood eosinophil ratio were positively correlated with hsa_circ_0005519 expression in CD4 + T cells. These outcomes were also different in asthmatic patients with low vs high hsa_circ_0005519 levels. Hsa_ circ_0005519 expressions between CD4 + T cells and PBMCs were concordant in asthmatic patients. Mechanistically, hsa_circ_0005519 might bind to hsa-let-7a-5p and relieve suppression for IL-13/IL-6 in CD4 + T cells. Conclusions and clinical relevance:Our data suggest that hsa_circ_0005519 may induce IL-13 and IL-6 expression by regulating hsa-let-7a-5p in CD4 + T cells to affect asthma. And hsa_circ_0005519 may be a potential biomarker of asthma. K E Y W O R D Sasthma, CD4 + T cells, hsa_circ_0005519, hsa-let-7a-5p, PBMCs

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IL-4/IL-13 Signaling Inhibits the Potential of Early Thymic Progenitors To Commit to the T Cell Lineage

Cited by 18 publications

References 42 publications

Induced Prostanoid Synthesis Regulates the Balance between Th1- and Th2-Producing Inflammatory Cytokines in the Thymus of Diet-Restricted Mice

Induced Prostanoid Synthesis Regulates the Balance between Th1- and Th2-Producing Inflammatory Cytokines in the Thymus of Diet-Restricted Mice

TCR signal strength controls thymic differentiation of iNKT cell subsets

Hsa_circ_0005519 increases IL‐13/IL‐6 by regulating hsa‐let‐7a‐5p in CD4⁺ T cells to affect asthma

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IL-4/IL-13 Signaling Inhibits the Potential of Early Thymic Progenitors To Commit to the T Cell Lineage

Cited by 18 publications

References 42 publications

Induced Prostanoid Synthesis Regulates the Balance between Th1- and Th2-Producing Inflammatory Cytokines in the Thymus of Diet-Restricted Mice

Induced Prostanoid Synthesis Regulates the Balance between Th1- and Th2-Producing Inflammatory Cytokines in the Thymus of Diet-Restricted Mice

TCR signal strength controls thymic differentiation of iNKT cell subsets

Hsa_circ_0005519 increases IL‐13/IL‐6 by regulating hsa‐let‐7a‐5p in CD4+ T cells to affect asthma

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Hsa_circ_0005519 increases IL‐13/IL‐6 by regulating hsa‐let‐7a‐5p in CD4⁺ T cells to affect asthma