Dataset Information

Increased Production of IL-17A-Producing ?? T Cells in the Thymus of Filaggrin-Deficient Mice.

ABSTRACT: Mutations in the filaggrin gene (Flg) are associated with increased systemic levels of Th17?cells and increased IL-17A production following antigen exposure in both humans and mice. In addition to Th17?cells, ?? T cells can produce IL-17A. The differentiation of ?? T cells to either IFN? or IL-17A-producing (??T17) cells is mainly determined in the thymus. Interestingly, it has been reported that filaggrin is expressed in the Hassall bodies in the human thymic medulla. However, whether filaggrin affects ?? T cell development is not known. Here, we show that filaggrin-deficient flaky tail (ft/ft) mice have an increased number of ??T17 cells in the spleen, epidermis, and thymus compared to wild-type (WT) mice. We demonstrate that filaggrin is expressed in the mouse thymic medulla and that blocking the egress of cells from the thymus results in accumulation of V?2+ ??T17 cells in the thymus of adult ft/ft mice. Finally, we find increased T cell receptor expression levels on ?? T cells and increased levels of IL-6 and IL-23 in the thymus of ft/ft mice. These findings demonstrate that filaggrin is expressed in the mouse thymic medulla and that production of V?2+ ??T17 cells is dysregulated in filaggrin-deficient ft/ft mice.

SUBMITTER: Jee MH

PROVIDER: S-EPMC5953325 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Publications

Increased Production of IL-17A-Producing γδ T Cells in the Thymus of Filaggrin-Deficient Mice.

Jee Mia Hamilton MH Johansen Jeanne Duus JD Buus Terkild Brink TB Petersen Trine Hilkjær TH Gadsbøll Anne-Sofie Østergaard AØ Woetmann Anders A Ødum Niels N Thyssen Jacob Pontoppidan JP White Andrea Jane AJ Anderson Graham G Geisler Carsten C Bonefeld Charlotte Menné CM

Frontiers in immunology 20180508

Mutations in the filaggrin gene (<i>Flg</i>) are associated with increased systemic levels of Th17 cells and increased IL-17A production following antigen exposure in both humans and mice. In addition to Th17 cells, γδ T cells can produce IL-17A. The differentiation of γδ T cells to either IFNγ or IL-17A-producing (γδT17) cells is mainly determined in the thymus. Interestingly, it has been reported that filaggrin is expressed in the Hassall bodies in the human thymic medulla. However, whether fi ...[more]

PMID: 29867965

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Project description:BackgroundStudies have revealed important roles for IL-17A in the development of acute lung injury (ALI) following sepsis. However, the mechanism underlying the regulation of lung IL-17A remains to be fully addressed. Recent studies suggested the effect of neuromedin U (NMU) on immune cell activation and the role of group 2 innate lymphoid cells (ILC2s) in the modulation of IL-17A production. We aimed to gain in-depth insight into the mechanism underlying sepsis-induced lung IL-17A production, particularly, the role of NMU in mediating neuronal regulation of ILC2s and IL-17A-producing γδ T cells activation in sepsis.MethodsWild type mice were subjected to cecal ligation and puncture (CLP) to induce sepsis with or without intraperitoneal injection of NMU. The levels of ILC2s, γδ T cells, IL-17A, NMU and NMU receptor 1 (NMUR1) in the lung were then measured. In order to determine the role of NMU signaling in ILC2 activation and the role of ILC2-released IL-9 in ILC2-γδ T cell interaction, ILC2s were sorted, and the genes of nmur1 and il9 in the ILC2s were knocked down using CRISPR/Cas9. The genetically manipulated ILC2s were then co-cultured with lung γδ T cells, and the levels of IL-17A from co-culture systems were measured.ResultsIn septic mice, the levels of NMU, IL-17A, ILC2s, and IL-17A-producing γδ T cells in the lung are significantly increased, and the expression of NMUR1 in ILC2s is increased as well. Exogenous NMU further augments these increases. The main source of IL-17A in response to CLP is γδ T cells, and lung nmur1 is specifically expressed in ILC2s. In vitro co-culture of ILC2s and γδ T cells leads to increased number of γδ T cells and higher production of IL-17A from γδ T cells, and these alterations are further augmented by septic treatment and exogenous NMU. Genetic knockdown of nmur1 or il9 in ILC2s attenuated the upregulation of γδ T cells and IL-17A production.ConclusionIn sepsis, NMU acting through NMUR1 in lung ILC2s initiates the ILC2 activation, which, in turn, promote IL-17A-producing γδ T cell expansion and secretion of IL-17A. ILC2-derived IL-9 plays an important role in mediating γδ T cell expansion and IL-17A production. This study explores a new mechanism underlying neuronal regulation of innate immunity in sepsis.

Dataset Information

Increased Production of IL-17A-Producing ?? T Cells in the Thymus of Filaggrin-Deficient Mice.

Publications

Increased Production of IL-17A-Producing γδ T Cells in the Thymus of Filaggrin-Deficient Mice.

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