Research ArticleDENDRITIC CELLS

Type I interferons drive the maturation of human DC3s with a distinct costimulatory profile characterized by high GITRL

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Science Immunology  13 Nov 2020:
Vol. 5, Issue 53, eabe0347
DOI: 10.1126/sciimmunol.abe0347

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Distinct dendritic cell responses

Dendritic cells (DCs) are critical for activating naïve T cells by presenting antigen and providing costimulation, processes that are enhanced by cytokine signals from the surrounding environment. Girard et al. used single-cell proteogenomics and flow cytometry to examine cell type–specific responses of human peripheral blood monocyte and DC subsets to type I interferon. IFN-β induced maturation of the recently identified CD1c+ CD5 DC3 subset, which was characterized by distinct expression of the costimulatory molecule GITRL, a TNF family ligand, and driven by NF-κB signaling. These results identify conserved and cell type–specific features of the type I interferon response of human mononuclear phagocyte subsets, including the molecular signals monocytes and DCs may leverage to instruct T cells.

Abstract

Human mononuclear phagocytes comprise specialized subsets of dendritic cells (DCs) and monocytes, but how these subsets individually regulate expression of the molecular signals involved in T cell costimulation is incompletely understood. Here, we used multiparameter flow cytometry and CITE-sequencing to investigate the cell type–specific responses of human peripheral blood DC and monocyte subsets to type I interferons (IFN-I), focusing on differential regulation of costimulatory molecules. We report that IFN-β drives the maturation of the recently identified human CD1c+ CD5 DC3 subset into cells with higher GITRL and lower CD86 expression compared with other conventional DC subsets. Transcriptomic analysis confirmed that DC3s have an intermediate phenotype between that of CD1c+ CD5+ DC2s and CD14+ monocytes, characterized by high expression of MHCII, Fc receptors, and components of the phagocyte NADPH oxidase. IFN-β induced a shared core response in human DC and monocyte subsets as well as subset-specific responses, including differential expression of costimulatory molecules. Gene regulatory network analysis suggests that upon IFN-β stimulation NFKB1 drives DC3s to acquire a maturation program shared with DC2s. Accordingly, inhibition of NF-κB activation prevented the acquisition of a mature phenotype by DC3s upon IFN-β exposure. Collectively, this study provides insight into the cell type–specific response of human DC and monocyte subsets to IFN-I and highlights the distinct costimulatory potential of DC3s.

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