IL-10 suppresses influenza-specific Th17 responses and is detrimental during high-dose primary challenge (43.8)

Abstract

Abstract Here we study the expression and influence of IL-10 during murine influenza infection. We find that IL-10 has a minimal impact on the outcome of sub-lethal infection but that IL-10-deficient mice display dramatically increased survival compared to wild-type mice when challenged with lethal doses of virus. Administration of IL-10 receptor blocking antibodies to wild-type mice results in a similar survival advantage. Increased survival in the absence of IL-10 does not correlate with increased cellular responses, or with decreased viral titers but does correlate with improved lung function and increased expression of Th17-associated cytokines during the peak of infection. Our studies identify highly activated, lung-resident virus-specific CD4 T cell effectors that co-produce IFNγ as the major source of IL-10 during primary influenza infection and we show that autocrine IL-10 production by responding CD4 T cells is critical in dampening influenza-specific Th17 responses. Finally, we show that transfer of virus-specific Th17-polarized CD4 T cell effectors can protect wild-type, B cell-deficient, and T cell-deficient mice against lethal influenza challenge. We further show that Th17-polarized effectors employ novel mechanisms of protection against influenza distinct from previously established modes of protection employed by Th1-polarized CD4 T cells. Our results thus show that production of IL-10 is detrimental during high-dose primary influenza challenge, and furthermore, suggest an unexpected protective role for virus-specific Th17 CD4 T cell effectors.