Abstract
Abstract Asthma is a chronic inflammatory disease in the lung mediated by allergen reactive Th2 type CD4 T cells producing the Th2 type cytokines. We recently reported that IL-27 plays a key role in Treg functions to control Th17-mediated autoimmune inflammation. However, a role for IL-27 in modulating Treg function during Th2-mediated allergic airway inflammation remains unclear. Here, we report that during cockroach antigen (CA)-induced allergic airway inflammation, IL-27 attenuates inflammatory responses primarily via Foxp3+ Tregs. Sensitizing mice with CA in alum followed by intranasal challenge induces allergic airway inflammation characterized by infiltration of eosinophils and effector CD4 T cells expressing Th2 cytokines in the lung. Recombinant IL-27 administration prior to antigen challenge significantly reduces the inflammation. Accumulation of CD4 T cells expressing inflammatory cytokines is dramatically reduced in the inflamed sites following IL-27 administration. However, IL-27-mediated treatment effects are completely lost when Foxp3+ Tregs are deleted prior to CA challenge. Adoptive transfer of wild type Tregs restores IL-27-mediated inhibition of airway inflammation, suggesting that Tregs may be the direct responders of IL-27. IL-27 stimulation in Tregs increases expression of lymphocyte activation gene 3 (Lag3), a surface molecule implicated in Treg functions. Unlike WT type cells, adoptive transfer of Tregs deficient in Lag3 fails to attenuate airway inflammation even after IL-27 administration. Taken together, these results demonstrate a novel IL-27-dependent Treg function to control allergic airway inflammation
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