IL-17 increases lung immunity and help lung host defense against K. pneumoniae infection

Bacterial pneumonia is now the most common pneumonia in patients with HIV infection with CD4 counts less than 500. However, the recent for a breech in anti-bacterial host defenses in the context of HIV infection remains unclear. IL-17 is a recently identified cytokine produced by activated CD4 T cells and has recently been shown to induce both TNF and IL-1 release from human monocytes. We hypothesized that IL-17 could augment lung anti-bacterial host defenses by local activation of lung macrophages. To overexpress IL-17 in the lung, we constructed a recombinant adenovirus vector encoding murine IL-17 cDNA (AdmlL-17). AdCMVLuc (encoding luciferase) served as the control vector. 10⁹ pfu of AdmlL-17 or AdCMVLuc was administered to 6-8 week old female C57BL/6 mice intratracheally (IT) or IV. In a subgroup of animals we administered an IT challenge of 10⁷ cfu of K. pneumoniae. IT AdmlL-17 was found to increase lung CD3+/4+ and CD3+/8+ positive cells compared to AdCMVLuc controls. Moreover, these T-cells had significant induction of CD25 compared to blood CD6+ T-cells suggesting induction of IL-2 receptor by IL-17. AdmlL-17 also resulted in a significant increase in lung neutrophils, which peaked on day 7 after gene transfer. Animals transduced with AdmlL-17 had significantly better clearance of K. pneumoniae after intrapulmonary challenge compared to PBS or AdCMVLuc controls. To investigate whether IL-17 could induce TNF production by mouse macrophages we incubated RAW 264.7 cells with varying concentrations of mlL-17 in vitro. In this assay, we observed a dose-dependent increase of TNF production by IL-17. Our data represent the first demonstration that 1). IL-17 can modulate and increase lung immunity by recruiting T cells to lung, increasing the percent of PMN in BALF and 2). IL-17 could increase lung host defenses against K. pneumoniae, which could be in part due to the induction of TNF-α by IL-17 in lung macrophages. IL-17 may represent a critical "cross-talk" cytokine between T-cells and macrophages.