IRF4-dependent DCs promote the establishment of CD8+ T cell memory during influenza infection.

Abstract

Abstract The transcription factor IRF4 governs the development and function of CD11b+ dendritic cells (DCs). To determine the role of IRF4-dependent DCs in influenza infection, we compared responses of wild-type and CD11c-cre-Irf4f/f(KO) mice. The KO mice lack one lung-resident CD11b+ DC subset, and the other DC subsets lack IRF4. Upon infection with A/PuertoRico/8/34 virus, KO lung DCs contained increased IL-12 and reduced IL-10 RNA, which correlated with elevated numbers of CD103+ lung migratory DCs in the mLN. Consistent with this, KO mice showed greater numbers of T-bet+ and IFNg+ influenza antigen-specific CD8+ and CD4+ T cells, reduced numbers of Foxp3+ T regulatory cells, and decreased numbers of CD8+ T memory precursor cells. These altered effector T cell populations in KO mice impacted the memory T cell response to influenza virus. Numbers of virus-specific lung resident memory CD8+ T cells were significantly reduced in KO mice. Upon challenge with heterosubtypic virus, KO mice showed deficient expansion of virus-specific IFNγ+ CD8+ T cells. Taken together, these data show that KO mice mount a stronger antiviral T cell response upon primary infection but then have a weaker CD8+ T cell memory response to heterosubtypic virus. This supports the hypothesis that during influenza infection, the functional responses of IRF4-dependent DCs lead to increased differentiation of CD8+ memory precursor T cells and numbers of lung resident CD8+memory T cells.