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

Sci Immunol. 2020 Nov 13;5(53):eabe0347. doi: 10.1126/sciimmunol.abe0347.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • B7-2 Antigen / metabolism
  • Cell Communication / genetics
  • Cell Communication / immunology*
  • Cell Separation
  • Cells, Cultured
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Flow Cytometry
  • Gene Regulatory Networks / immunology
  • Healthy Volunteers
  • Humans
  • Interferon-beta / metabolism*
  • NF-kappa B p50 Subunit / metabolism*
  • Primary Cell Culture
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Tumor Necrosis Factors / metabolism*

Substances

  • B7-2 Antigen
  • CD86 protein, human
  • NF-kappa B p50 Subunit
  • NFKB1 protein, human
  • TNFSF18 protein, human
  • Tumor Necrosis Factors
  • Interferon-beta