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IL-10 Deficiency Unleashes an Influenza-Specific Th17 Response and Enhances Survival against High-Dose Challenge¹

K. Kai McKinstry^2,3,*, Tara M. Strutt^2,*, Amanda Buck^*, Jonathan D. Curtis^*, John P. Dibble^*, Gail Huston^*, Michael Tighe^*, Hiromasa Hamada^*, Stewart Sell, Richard W. Dutton^* and Susan L. Swain^*

^* Trudeau Institute, Saranac Lake, NY 12983; and Wadsworth Center and Ordway Research Institute, Albany, NY 12208

We examined the expression and influence of IL-10 during influenza infection. We found that IL-10 does not impact sublethal infection, heterosubtypic immunity, or the maintenance of long-lived influenza Ag depots. However, IL-10-deficient mice display dramatically increased survival compared with wild-type mice when challenged with lethal doses of virus, correlating with increased expression of several Th17-associated cytokines in the lungs of IL-10-deficient mice during the peak of infection, but not with unchecked inflammation or with increased cellular responses. Foxp3^– CD4 T cell effectors at the site of infection represent the most abundant source of IL-10 in wild-type mice during high-dose influenza infection, and the majority of these cells coproduce IFN-. Finally, compared with predominant Th1 responses in wild-type mice, virus-specific T cell responses in the absence of IL-10 display a strong Th17 component in addition to a strong Th1 response and we show that Th17-polarized CD4 T cell effectors can protect naive mice against an otherwise lethal influenza challenge and utilize unique mechanisms to do so. Our results show that IL-10 expression inhibits development of Th17 responses during influenza infection and that this is correlated with compromised protection during high-dose primary, but not secondary, challenge.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants AI46530 and AI067294 (to S.L.S.) and NS06104, by the Department of Defense HR+3222, and by the Trudeau Institute.

² K.K.M. and T.M.S. contributed equally.

³ Address correspondence and reprint requests to Dr. K. Kai McKinstry, Trudeau Institute, 154 Algonquin Avenue, Saranac Lake, NY, 12983. E-mail address: kmckinstry{at}trudeauinstitute.org

⁴ Abbreviations used in this paper: KO, knockout; WT, wild type; EID, egg infective dose; dLN, draining lymph node; Tc, T cytotoxic cell; LCMV, lymphocytic choriomeningitis virus; Tg, transgenic; ICCS, intracellular cytokine staining; ROR, retinoid-related orphan receptor.

⁵ The online version of this article contains supplemental material.

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