Single-Cell Analysis of Diverse Pathogen Responses Defines a Molecular Roadmap for Generating Antigen-Specific Immunity

• Published in: Cell systems Vol. 8; no. 2; pp. 109 - 121.e6
• Main Authors: Blecher-Gonen, Ronnie, Bost, Pierre, Hilligan, Kerry L., David, Eyal, Salame, Tomer Meir, Roussel, Elsa, Connor, Lisa M., Mayer, Johannes U., Bahar Halpern, Keren, Tóth, Beáta, Itzkovitz, Shalev, Schwikowski, Benno, Ronchese, Franca, Amit, Ido
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.02.2019; Elsevier
• Subjects: Animals; antigen-presenting cells; cell-cell communication; dendritic cells; Human health and pathology; Humans; IFN-γ; Immunity, Innate; Immunity, Innate - immunology; Immunology; Infectious diseases; innate immune cells; Life Sciences; lymph node; Mice; monocytes; NK cells; Single-Cell Analysis; Single-Cell Analysis - methods; single-cell RNA-seq; T cell polarization; monocytes; NK cells; IFN-γ; dendritic cells; antigen-presenting cells; innate immune cells; lymph node; T cell polarization; single-cell RNA-seq; cell-cell communication
• ISSN: 2405-4712; 2405-4720
• DOI: 10.1016/j.cels.2019.01.001

The immune system generates pathogen-tailored responses. The precise innate immune cell types and pathways that direct robust adaptive immune responses have not been fully characterized. By using fluorescent pathogens combined with massively parallel single-cell RNA-seq, we comprehensively characterized the initial 48 h of the innate immune response to diverse pathogens. We found that across all pathogens tested, most of the lymph node cell types and states showed little pathogen specificity. In contrast, the rare antigen-positive cells displayed pathogen-specific transcriptional programs as early as 24 h after immunization. In addition, mycobacteria activated a specific NK-driven IFNγ response. Depletion of NK cells and IFNγ showed that IFNγ initiated a monocyte-specific signaling cascade, leading to the production of major chemokines and cytokines that promote Th1 development. Our systems immunology approach sheds light on early events in innate immune responses and may help further development of safe and efficient vaccines. [Display omitted] •scRNA-seq of pathogen-challenged lymph node identifies key cell types and pathways•Antigen-specific immunity is driven by antigen-carrying dendritic cells and monocytes•Antigen-specific cytokines drive population heterogeneity at the cellular level•Crosstalk between monocytes and NK cells promotes the induction of Th1 response Single-cell analysis of lymph node response to diverse pathogen challenges reveals that antigen-specific immunity is driven by transcriptional changes that are mostly restricted to antigen-carrying dendritic and monocyte populations, suggesting their key role in the initiation of immune responses.