Nature 441, 235C238 (2006). Moreover, inhalation of 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 T17 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. INTRODUCTION Recent evidence shows that T cells can regulate innate immunity,1 such as memory T cells facilitating innate immune cell recruitment amplifying local immunity.2C4 Although acute lung injury and acute respiratory distress syndrome (ALI/ARDS) have been considered to be driven by the innate immune response, evidence for the participation of T cells is emerging. Consistent with a role for T cells in ALI/ARDS, several reports observed a significant increase in CD4 and CD8 T cells expressing activation and proliferation markers in bronchoalveolar lavage (BAL) of patients during the early phase of ARDS.5, 6 Moroever, specific PI-1840 T cells drive lung injury in mice after inhalation of enterotoxin.7C9 Importantly, interleukin (IL)-2 is regarded as a biomarker for ARDS severity.10, 11 When IL-2 is given therapeutically to cancer patients it FLT3 carries a known risk PI-1840 of lung injury that is largely indistinguishable from that seen in sepsis.12, 13 Similarly, IL-2 administration to rats induces pulmonary inflammation.14, 15 Altogether these observations suggest a role for T cells and IL-2 in ALI/ARDS. infection contributes to higher morbidity/mortality during influenza coinfection16 and healthcare-associated pneumonia,17 and is a major cause of ARDS associated with pneumonia.18, 19 Host defense against lung infection has been shown to be mediated by T cells.20 This might be related to the role of T cells as a primary source of IL-17, which facilitates bacterial clearance, but also contributes to lung injury during lung infection. A major virulence mechanism of is the release of enterotoxins that are well known to induce lethal toxic shock in people.21, 22 These enterotoxins are regarded as superantigens since, without being processed, they bind MHC II and link specific V regions of the TCR on T cells to drive massive production of cytokines and proliferation.23C25 We recently demonstrated that after enterotoxin A inhalation, lung T cells produced IL-17, even though they are not known to bind enterotoxin A, but interestingly they required T cells for their activation.26 Here, we describe how T cells induce pulmonary T-cell activation. The data demonstrate that enterotoxins induce rapid release of IL-2, which activates pulmonary T cells to synthesize pro-inflammatory IL-17. Ex vivo culture of pulmonary T cells with IL-2 -induced IL-17 production and CyTOF analysis demonstrated STAT5 activation and RoRt expression within a small subpopulation of granular T17 cells. This contrasts from the antagonizing role IL-2 plays in Th17 differentiation,27 and shows that IL-17 release from T17 cells is JAK/STAT dependent. Mechanistically, we found that IL-2 worked in concert with IL-1 to drive IL-17 production by both bulk and sorted lung T cells. Thus, our data suggests that high levels of IL-2 activates T17 cells, producing IL-17 driven pulmonary injury. Moreover, IL-2 cancer immunotherapy could be void of adverse IL-17-based events with the use of IL-17 PI-1840 blockade. MATERIALS AND METHODS Mice C57BL/6 and caspase 1/11?/? (stock #16621) mice were purchased from the Jackson Laboratory (Bar Harbor, ME). Caspase 11?/? mice were the kind gift of Vishva Dixit (Genentech) and Kate Fitzgerald (University of Massachusetts Medical School). All mice were maintained in the central animal facility at the University of Connecticut Health (UCH) in PI-1840 accordance with federal guidelines. The present study was approved by the UCHs Animal Care Committee. Reagents enterotoxin A (enterotoxin A) was purchased from Toxin Technology Inc. (Sarasota, FL). Mouse recombinant IL-1 was purchased from Life Technologies (Carlsbad, CA). Human rIL-2 was obtained from the NIH. Ionomycin was purchased from Life Technology (Grand Island, NY). Phorbol 12-Myristate 13-Acetate (PMA).