IL-33 administration promotes both Th2 and Th17 responses and improves resolution during influenza infection (92.7)

Abstract

Abstract A number of acute and chronic immunopathological diseases are driven by excessive Th1 cytokine responses. During influenza infection, Th1 cells and CTL dominate in the lungs. Whilst important for viral clearance, these cells may also cause damaging immune pathology. We now show for the first time that a newly-described cytokine, IL-33, drives Th2 cell polarization during influenza infection, and may be used to counter excessive pathology caused by Th1 cells. We show a change in expression of both endogenous IL-33 and its receptor, ST2L, in the influenza-inflamed lung. IL-33 administration improves resolution of disease and reduces the number of TNF-α and IFN-γ-secreting CD4 and CD8 T cells in the airways of influenza-infected animals. Critically, this reduction in anti-viral T cell number does not impair viral clearance nor alter the recall response. Surprisingly, IL-33 treatment during influenza infection also promotes Th17 cell development. Our data suggest that IL-33 mediates these effects via respiratory epithelium-derived TSLP. This interaction drives a Th17-promoting cytokine cascade involving IL-23 and IL-21. Though viral-induced illness is lessened by IL-33 treatment alone, further improvements are observed when IL-33 is given in combination with IL-17A depletion. These results have important implications for pathologies associated with both Th1 and Th17 cytokine profiles and may explain how an increase of IL-33 correlates with a worsening of disease.