IL-10 deficiency unleashes an influenza-specific Th17 response and enhances survival against high-dose challenge.
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-gamma. 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.
McKinstry
K Kai
KK
Trudeau Institute, Saranac Lake, NY 12983, USA.
Strutt
Tara M
TM
Buck
Amanda
A
Curtis
Jonathan D
JD
Dibble
John P
JP
Huston
Gail
G
Tighe
Michael
M
Hamada
Hiromasa
H
Sell
Stewart
S
Dutton
Richard W
RW
Swain
Susan L
SL
D000818:Animals; D000956:Antigens, Viral / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000276:immunology; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D016753:Interleukin-10 / Q000172:deficiency* / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology*; D051379:Mice; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015996:Survival Rate; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
D000956:Antigens, Viral; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D020381:Interleukin-17; D016753:Interleukin-10