*3.4. Th17 Cells*

Th17 cells are a subset of CD4+ helper T cells that produce the cytokines IL-17A, IL-17F, IL-21, and IL-22. The differentiation of naïve CD4+ T cells into Th17 cells requires the expression of TGF-β and IL-6 in mice, or TGF-β, IL-1 β, and IL-21 in humans [28]. When IL-17A and IL-17F are produced from Th17 cells, they act in a proinflammatory role and can induce other proinflammatory cytokines, such as IL-8, from the airway epithelium, resulting in neutrophil recruitment. IL-17A and IL-17F also can elicit smooth muscle contraction and airway mucus metaplasia. Both cytokines are increased in the airways of patients with severe asthma [28].

Eicosanoids clearly regulate the production of Th17 cytokines. COX-2 KO mice had significantly reduced numbers of Th17 cells in the lungs, BALF, and spleen following ovalbumin-sensitization and challenge compared to WT mice [28]. Further, IL-17A and IL-6 levels in the blood and BALF were markedly reduced in COX-2 KO mice relative to WT mice following the allergen challenge [28]. These investigators also examined the roles of several different prostaglandins in Th17 differentiation and demonstrated that prostacyclin increased Th17 differentiation in cells that express COX-2 and partially restored Th17 differentiation in mice that were deficient for COX-2 [28]. This finding was corroborated by another group that reported that when iloprost and cicaprost administration in the presence of IL-23 promoted Th17 differentiation and survival in vitro [29]. When prostacyclin analogs were administered in vitro to naïve CD4+ T cells from WT mice, they stimulated greater production of both IL-17A and IL-22 compared to vehicle treatment, indicating that the analogs supported Th17 differentiation and revealing another facet in prostacyclin's role in allergic inflammation [29].

γδ T cells have a first-line immunoprotective role against pathogens and environmental irritants in mucosal tissues [30]. A subset of γδ T cells, γδ-17 cells, produce IL-17. IP KO mice challenged by ovalbumin had a significant reduction in the amount of γδ-17 cells compared to WT mice, and iloprost augmented IL-17 production by γδ T cells, reflecting that both prostacyclin analogs and prostacyclin signaling play a key role in γδ T cell development and effector function [30].
