Abstract
Th1 cells control their activity by producing regulatory IL-10. Here we report that Th1 cell-derived IL-10 facilitates their expansion and, in addition, augments Th1 cell production of IFN-γ, TNF-α and IL-2 during the early phase of influenza. In our antigen-specific mouse experimental system, influenza haemagglutinin-specific CD4(+) T cells respond to infection with the induction of T-bet, and produce both IFN-γ and IL-10. In the early phase of infection, an abundance of viral neuraminidase causes TGF-β activation of haemagglutinin-specific CD4(+) T cells. CD4(+) T-cell-derived IL-10 inhibits neuraminidase-driven TGF-β activation and counteracts the virus-mediated immune suppression. As the host eradicates the virus, neuraminidase activity wanes and IL-10 receptors are upregulated on CD4(+) T cells in the late phase of infection. IL-10 then suppresses immune activation and aids in recovery from infection and inflammation. These results reveal a previously unrecognized function of Th1 cell-derived IL-10 in vivo.
Highlights
Th1 cells control their activity by producing regulatory IL-10
Our findings demonstrate how Th1 cellderived IL-10 performs to counteract viral immune suppression and augment inflammation during the early phase of influenza virus infection
The 6.5 HA-specific CD4 þ T cells responded to infection with the production of Th1 cytokines IFN-g, TNF-a and IL-2, along with increased levels of IL-10 (Supplementary Fig. 1a)
Summary
Influenza virus infection drives an HA-specific Th1 response. In our influenza HA antigen-specific mouse model[20], syngeneic mice received 2.5 Â 106 naive 6.5 HA-specific CD4 þ T cells by adoptive transfer. When the virus multiplied during the early phase of influenza virus infection in the IL-10 KO mice, viral NA desialylated the surface of IL-10 KO HA-specific CD4 þ T cells and caused the release of active TGF-b from day 2 to day 4 post infection, similar to the WT cells in WT mice (Fig. 1a–c). The viral NA-driven activation of TGF-b was not restricted in the antigen-specific CD4 þ T cells in the lungs of influenza virus-infected mice. In the early phase of infection, IL-10 treatment enhanced the clonotypic expansion and the cytokine production of IL-10 KO HA-specific CD4 þ T cells adoptively transferred into IL-10 KO mice. With supplemented IL-10 during the early phase of infection, daily from day 0 to day 3, the clonotypic percentage of HA-specific CD4 þ T cells was increased from 1.48±0.4 to 3.64±0.3 in the lungs of the IL-10 KO adoptive transfer set. Without adoptive transfer of antigen-specific CD4 þ T cells, IL-10 still supported T-cell activation in both IL-10 KO and WT
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