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T cell-directed IL-17 production by lung granular ?? T cells is coordinated by a novel IL-2 and IL-1? circuit.

ABSTRACT: Immune-mediated lung is considered the result of an exacerbated innate injury immune response, although a role for adaptive lymphocytes is emerging. ?? T cells specific for S. aureus enterotoxin A orchestrate a T??17 response during lung injury. However, the mechanism driving IL-17 production is unclear. Here, we show a role for IL-2 triggering IL-17 production by lung granular ?? T cells as IL-17 synthesis and neutrophil recruitment was reduced by IL-2 blocking mAbs in vitro and in vivo. Mass cytometry analysis revealed that lung ?? T cells responded directly to IL-2 as evident from STAT5 phosphorylation and RoR?t expression. IL-2 receptor blocking mAbs and JAK inhibition impaired STAT5 phosphorylation and IL-17 release. Moreover, inhalation of S. aureus enterotoxin A induced IL-2 secretion and caspase-1-dependent IL-1? activation to drive IL-17 production. This T-cell-mediated inflammasome-dependent IL-17 response is maximum when lung T??17 cells were sequentially stimulated first with IL-2 then IL-1?. Interestingly, when IL-2 is given therapeutically to cancer patients it carries a known risk of lung injury that is largely indistinguishable from that seen in sepsis. Hence, this novel mechanism reveals therapeutic targets treating both acute lung injury and high-dose IL-2 toxicity in cancer.

SUBMITTER: Menoret A

PROVIDER: S-EPMC6668340 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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T cell-directed IL-17 production by lung granular γδ T cells is coordinated by a novel IL-2 and IL-1β circuit.

Ménoret Antoine A Buturla James A JA Xu Maria M MM Svedova Julia J Kumar Sanjeev S Rathinam Vijay A K VAK Vella Anthony T AT

Mucosal immunology 20180615 5

Immune-mediated lung is considered the result of an exacerbated innate injury immune response, although a role for adaptive lymphocytes is emerging. αβ T cells specific for S. aureus enterotoxin A orchestrate a Tγδ17 response during lung injury. However, the mechanism driving IL-17 production is unclear. Here, we show a role for IL-2 triggering IL-17 production by lung granular γδ T cells as IL-17 synthesis and neutrophil recruitment was reduced by IL-2 blocking mAbs in vitro and in vivo. Mass c ...[more]

PMID: 29907868

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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

T cell-directed IL-17 production by lung granular ?? T cells is coordinated by a novel IL-2 and IL-1? circuit.

Publications

T cell-directed IL-17 production by lung granular γδ T cells is coordinated by a novel IL-2 and IL-1β circuit.

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