Cytokine Regulation of Lung Th17 Response to Airway Immunization using LPS Adjuvant

Infections caused by bacteria in the airway preferentially induce a Th17 response. However the mechanisms involved in the regulation of CD4 T cells responses in the lungs are incompletely understood. Here we have investigated the mechanisms involved in the regulation of Th17 differentiation in the lungs in response to immunization with LPS as adjuvant. Our data shows that both Myd88 and TRIF are necessary for Th17 induction. This distinctive fate determination can be accounted for by the pattern of inflammatory cytokines induced by airway administration of LPS. We identified the production of IL-1β and IL-6 by small macrophages and IL-23 by alveolar dendritic cells, favoring Th17 responses, and IL-10 repressing IFN-γ production. Furthermore, we show that exogenous IL-1β can drastically alter Th1 responses driven by influenza and lymphocytic choriomeningitis virus infection models and induce IL-17 production. Thus the precision of the lung immune responses to potential threats is orchestrated by the cytokine microenvironment, can be repolarized and targeted therapeutically by altering the cytokine milieu. These results indicate how the development of Th17 responses in the lung are regulated by the cytokines produced by lung dendritic cells and macrophages in response to intranasal immunization with LPS adjuvant.