T Cell-Directed IL-17 production by Lung Granular γδ T cells is Coordinated by a Novel IL-2 and IL-1β Circuit

Abstract

Immune-mediated lung injury is considered the result of an exacerbated innate immune response, although a role for adaptive lymphocytes is emerging. αβ T cells specific for S. aureus enterotoxin A orchestrates a typical innate-like Tγδ17 response during lung injury. However, the mechanism by which a specific T cell response drives an innate immune response in the lung is unclear. Here, we show a role for IL-2 triggering IL-17 production by lung granular γδ T cells as IL-17 synthesis was reduced by IL-2 blocking mAbs in vitro and in vivo. Granular γδ T cells in the lung constitute a rare population, hence Mass Cytometry (CyTOF) was utilized to characterize this population. CyTOF 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. Further investigation is still needed to identify the cellular source of 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.