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

Mucosal Immunol. 2018 Sep;11(5):1398-1407. doi: 10.1038/s41385-018-0037-0. Epub 2018 Jun 15.

Abstract

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 cytometry analysis revealed that lung γδ T cells responded directly to IL-2 as evident from STAT5 phosphorylation and RoRγt 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-1β activation to drive IL-17 production. This T-cell-mediated inflammasome-dependent IL-17 response is maximum when lung Tγδ17 cells were sequentially stimulated first with IL-2 then IL-1β. 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Caspase 1 / immunology
  • Interleukin-17 / immunology*
  • Interleukin-1beta / immunology*
  • Interleukin-2 / immunology*
  • Janus Kinases / immunology
  • Lung / immunology*
  • Lung / microbiology
  • Mice
  • Mice, Inbred C57BL
  • Neutrophils / immunology
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / immunology
  • Phosphorylation / immunology
  • STAT5 Transcription Factor / immunology
  • Saccharomyces cerevisiae / immunology
  • T-Lymphocytes / immunology*

Substances

  • Antibodies, Monoclonal
  • Interleukin-17
  • Interleukin-1beta
  • Interleukin-2
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • STAT5 Transcription Factor
  • Janus Kinases
  • Caspase 1