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

Abstract

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-γ. 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.

Memory CD4+T-cell–mediated protection depends on secondary effectors that are distinct from and superior to primary effectors

“…from either in vitro or in vivo memory cells, produced IL-10 ( Fig. 4G), consistent with the lack of IL-10 observed in our earlier studies of memory CD4 + T-cell responses against IAV (9). A reciprocal pattern was found for IL-17 production.…”

“…The transfer of 1°effectors to unprimed mice can protect against lethal challenge (8)(9)(10), and studies demonstrating memory CD4 + T-cell protection in mice deficient for CD8 + T and B cells suggest that an important helper-independent protective contribution of memory CD4 + T cells may be mediated directly by the 2°e ffectors (11)(12)(13). In addition, IAV-specific 1°effector (7,10) and memory (14,15) CD4 + T cells isolated from the lung and from secondary lymphoid organs (SLO) display distinct functional and phenotypic characteristics.…”

“…We have shown that IL-10 production by 1°CD4 + T-cell effectors can impede protection against IAV, whereas IL-17 + T cells can contribute to viral clearance (9,22). We concentrated on lungresident effectors, because the expression of both IL-10 and IL-17 from CD4 + T cells is restricted largely to the lung during IAV infection, with production of both IL-10 and IL-17 peaking at 7 dpi (9).…”

IL-10 inhibits neuraminidase-activated TGF-β and facilitates Th1 phenotype during early phase of infection

“…In experimental mice, IL-10 seems to aggravate the disease. IL-10 knockout (KO) mice survive better than wild-type (WT) mice upon infection with influenza virus 21,22 . However, IL-10 receptor (IL-10R) blockade after 3 days of infection increases mortality with aggravated pulmonary inflammation in mice 19 .…”

Current prospects and future challenges for nasal vaccine delivery

“…40 Later research has indicated that the response is more nuanced, with some contradictory evidence regarding advantages and disadvantages of IL-17A induction. 41,42,43 Predominance of one set of cytokines over the other is generally indicative of polarization of Th responses, for example the presence of IL-4 and absence of IFN-g indicate a classical Th-2 polarized immune reaction 44 although these cytokines can also be released at the same time. 45,46,47 The varying cytokine profiles related to CTL and antibody production are fundamental in affording protection against a specific pathogen.…”