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Suppressor of cytokine signaling (SOCS) proteins are inducible feedback inhibitors of cytokine signaling. SOCS1 −/−  mice die within three weeks postnatally due to IFN-γ-induced hyperinflammation. Since it is well established that IFN-γ is dispensable for protection against influenza infection, we generated SOCS1 −/− IFN-γ −/−  mice to determine whether SOCS1 regulates antiviral immunity in vivo. Here we show that SOCS1 −/− IFN-γ −/−  mice exhibited significantly enhanced resistance to influenza infection, as evidenced by improved viral clearance, attenuated acute lung damage, and consequently increased survival rates compared to either IFN-γ −/−  or WT animals. Enhanced viral clearance in SOCS1 −/− IFN-γ −/−  mice coincided with a rapid onset of adaptive immune responses during acute infection, while their reduced lung injury was associated with decreased inflammatory cell infiltration at the resolution phase of infection. We further determined the contribution of SOCS1-deficient T cells to antiviral immunity. Anti-CD4 antibody treatment of SOCS1 −/− IFN-γ −/−  mice had no significant effect on their enhanced resistance to influenza infection, while CD8 +  splenocytes from SOCS1 −/− IFN-γ −/−  mice were sufficient to rescue RAG1 −/−  animals from an otherwise lethal infection. Surprisingly, despite their markedly reduced viral burdens, RAG1 −/−  mice reconstituted with SOCS1 −/− IFN-γ −/−  adaptive immune cells failed to ameliorate influenza-induced lung injury. In conclusion, in the absence of IFN-γ, the cytoplasmic protein SOCS1 not only inhibits adaptive antiviral immune responses but also exacerbates inflammatory lung damage. Importantly, these detrimental effects of SOCS1 are conveyed through discrete cell populations. Specifically, while SOCS1 expression in adaptive immune cells is sufficient to inhibit antiviral immunity, SOCS1 in innate/stromal cells is responsible for aggravated lung injury.

Expression of Suppressor of Cytokine Signaling 1 (SOCS1) Impairs Viral Clearance and Exacerbates Lung Injury during Influenza Infection