IRF4-dependent dendritic cells regulate CD8(+) T cell differentiation and memory responses in influenza infection

Acute respiratory disease caused by influenza viruses is imperfectly mitigated by annual vaccination to select strains. Development of vaccines that elicit lung-resident memory CD8(+) T cells (T(RM)) would offer more universal protection to seasonal and emerging pandemic viruses. Understanding how lung-resident dendritic cells (DCs) regulate T(RM) differentiation would be an important step in this process. Here, we used CD11c-cre-Irf4(f/f) (KO) mice, which lack lung-resident IRF4-dependent CD11b(+)CD24(hi) DCs and show IRF4 deficiency in other lung cDC subsets, to determine if IRF4-expressing DCs regulate CD8(+) memory precursor cells and T(RM) during influenza A virus (IAV) infection. KO mice showed defective CD8(+) T cell memory, stemming from a deficit of T regulatory cells and memory precursor cells with decreased Foxo1 expression. Transfer of wild-type CD11b(+)CD24(hi) DCs into KO mice restored CD8(+) memory precursor cell numbers to wild-type levels. KO mice recovered from a primary infection harbored reduced numbers of CD8(+) T(RM) and showed deficient expansion of IFNγ(+)CD8(+) T cells and increased lung pathology upon challenge with heterosubtypic IAV. Thus, vaccination strategies that harness the function of IRF4-dependent DCs could promote the differentiation of CD8(+) T(RM) during IAV infection.