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.