IRF4-dependent DCs regulate T cell effector and memory responses in influenza virus infection

Abstract

Abstract Dendritic cells (DCs) activate adaptive immune responses during respiratory virus infection. A number of transcription factors govern the development and function of tissue DCs, including IRF4. To determine the role of IRF4-dependent lung DCs in influenza virus infection, we studied CD11c-cre-Irf4f/f (KO) mice. In this KO, one lung resident CD11b+ DC subset is missing, 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. This altered IL-12/IL-10 balance in KO mice led to increased numbers of T-bet+ IFNg+ influenza antigen-specific effector CD8+ and CD4+ T cells, yet reduced numbers of Foxp3+ T regulatory cells (Tregs) and CD8+ antigen-specific memory precursor effector cells (MPECs) at later stages of infection. The remaining MPECs in KO mice showed decreased expression of Foxo1 and Bcl6, key transcription factors important for T cell memory differentiation. This suggests that factors including IL-10 produced by IRF4-dependent DCs elicit a memory-biased transcriptional program in late CD8+ T cell effectors. Accordingly, KO lungs contained reduced numbers of resident CD8+ memory T cells (TRM) forty days post-infection. Upon rechallenge 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 elaborate a weaker CD8+ T cell memory response to heterologous virus. Our data support the hypothesis that IRF4-dependent DCs normally act to promote the differentiation of CD8+ memory T cells during influenza virus infection.