Inflammatory Type 2 cDCs Acquire Features of cDC1s and Macrophages to Orchestrate Immunity to Respiratory Virus Infection

• Published in: Immunity (Cambridge, Mass.) Vol. 52; no. 6; pp. 1039 - 1056.e9
• Main Authors: Bosteels, Cedric, Neyt, Katrijn, Vanheerswynghels, Manon, van Helden, Mary J., Sichien, Dorine, Debeuf, Nincy, De Prijck, Sofie, Bosteels, Victor, Vandamme, Niels, Martens, Liesbet, Saeys, Yvan, Louagie, Els, Lesage, Manon, Williams, David L., Tang, Shiau-Choot, Mayer, Johannes U., Ronchese, Franca, Scott, Charlotte L., Hammad, Hamida, Guilliams, Martin, Lambrecht, Bart N.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.06.2020; Elsevier Limited
• Subjects: Antigen Presentation; Antigen-presenting cells; Antigens; Biomarkers; CD4 antigen; CD64; CD8 antigen; Cell culture; Cell Plasticity - immunology; Chemokines; convalescent serum; dendritic cell; Dendritic cells; Dendritic Cells - immunology; Dendritic Cells - metabolism; Disease Susceptibility; Fc receptor; Fc receptors; Gene Expression Profiling; Gene Expression Regulation; Gene Regulatory Networks; Immunity; Immunophenotyping; inf-cDC2; Infections; Inflammation; Interferon; Interferon regulatory factor 4; Interferon Type I - metabolism; IRF8; Kinases; Lungs; Lymphocytes; Lymphocytes T; Macrophages; Macrophages - immunology; Macrophages - metabolism; monocyte; Monocytes; Monocytes - immunology; Monocytes - metabolism; Organ Specificity - immunology; Population; Receptors; Receptors, Fc - metabolism; Respirovirus Infections - etiology; Respirovirus Infections - metabolism; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Toll-like receptors; transcription factor; Transcription Factors; type 1 interferon; Viral infections; virus; Virus Diseases - genetics; Virus Diseases - immunology; Virus Diseases - metabolism; Virus Diseases - virology; Viruses; CD64; type 1 interferon; transcription factor; inf-cDC2; Fc receptor; convalescent serum; inflammation; monocyte; IRF8; virus; dendritic cell
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2020.04.005

The phenotypic and functional dichotomy between IRF8+ type 1 and IRF4+ type 2 conventional dendritic cells (cDC1s and cDC2s, respectively) is well accepted; it is unknown how robust this dichotomy is under inflammatory conditions, when additionally monocyte-derived cells (MCs) become competent antigen-presenting cells (APCs). Using single-cell technologies in models of respiratory viral infection, we found that lung cDC2s acquired expression of the Fc receptor CD64 shared with MCs and of IRF8 shared with cDC1s. These inflammatory cDC2s (inf-cDC2s) were superior in inducing CD4+ T helper (Th) cell polarization while simultaneously presenting antigen to CD8+ T cells. When carefully separated from inf-cDC2s, MCs lacked APC function. Inf-cDC2s matured in response to cell-intrinsic Toll-like receptor and type 1 interferon receptor signaling, upregulated an IRF8-dependent maturation module, and acquired antigens via convalescent serum and Fc receptors. Because hybrid inf-cDC2s are easily confused with monocyte-derived cells, their existence could explain why APC functions have been attributed to MCs. [Display omitted] •Type I interferon drives differentiation of inf-cDC2s that closely resemble MCs•Inf-cDC2s prime CD4+ and CD8+ T cells, whereas MCs lack APC function•Inf-cDC2s internalize antibody-complexed antigen via Fc receptors•IRF8 controls maturation gene module in inf-cDC2s The dichotomy between type 1 and 2 conventional DCs under steady-state conditions is well defined. Bosteels et al. demonstrate that, upon inflammation, cDC2s acquire a hybrid inf-cDC2 phenotype, sharing phenotype, gene expression, and function with cDC1s and monocyte-derived cells, to optimally boost CD4 and CD8 immunity via Fc receptors.