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Aire Inhibits the Generation of a Perinatal Population of Interleukin-17A-Producing ?? T Cells to Promote Immunologic Tolerance.

ABSTRACT: Aire's primary mechanism of action is to regulate transcription of a battery of genes in medullary thymic epithelial cells (mTECs) and, consequently, negative selection of effector T cells and positive selection of regulatory T cells. We found that Aire-deficient mice had expanded thymic and peripheral populations of perinatally generated IL-17A+V?6+V?1+ T cells, considered to be "early responders" to tissue stress and drivers of inflammatory reactions. Aire-dependent control of Il7 expression in mTECs regulated the size of thymic IL-17A+V?6+V?1+ compartments. In mice lacking Aire and ?? T cells, certain tissues typically targeted in the "Aire-less" disease, notably the retina, were only minimally infiltrated. IL-17A+V?6+V?1+ cells were present in the retina of wild-type mice and expanded very early in Aire-deficient mice. A putatively parallel population of IL-17A+V?9+V?2+ T cells was increased in humans lacking Aire. Thus, Aire exerts multi-faceted autoimmune control that extends to a population of innate-like T cells.

SUBMITTER: Fujikado N

PROVIDER: S-EPMC5133707 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Aire Inhibits the Generation of a Perinatal Population of Interleukin-17A-Producing γδ T Cells to Promote Immunologic Tolerance.

Fujikado Noriyuki N Mann Alexander O AO Bansal Kushagra K Romito Kimberly R KR Ferre Elise M N EMN Rosenzweig Sergio D SD Lionakis Michail S MS Benoist Christophe C Mathis Diane D

Immunity 20161101 5

Aire's primary mechanism of action is to regulate transcription of a battery of genes in medullary thymic epithelial cells (mTECs) and, consequently, negative selection of effector T cells and positive selection of regulatory T cells. We found that Aire-deficient mice had expanded thymic and peripheral populations of perinatally generated IL-17A+Vγ6+Vδ1+ T cells, considered to be "early responders" to tissue stress and drivers of inflammatory reactions. Aire-depe ...[more]

PMID: 27851927

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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

Aire Inhibits the Generation of a Perinatal Population of Interleukin-17A-Producing ?? T Cells to Promote Immunologic Tolerance.

Publications

Aire Inhibits the Generation of a Perinatal Population of Interleukin-17A-Producing γδ T Cells to Promote Immunologic Tolerance.

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