Maturing Human CD127+ CCR7+ PDL1+ Dendritic Cells Express AIRE in the Absence of Tissue Restricted Antigens

Front Immunol. 2019 Jan 14;9:2902. doi: 10.3389/fimmu.2018.02902. eCollection 2018.

Abstract

Expression of the Autoimmune regulator (AIRE) outside of the thymus has long been suggested in both humans and mice, but the cellular source in humans has remained undefined. Here we identify AIRE expression in human tonsils and extensively analyzed these "extra-thymic AIRE expressing cells" (eTACs) using combinations of flow cytometry, CyTOF and single cell RNA-sequencing. We identified AIRE+ cells as dendritic cells (DCs) with a mature and migratory phenotype including high levels of antigen presenting molecules and costimulatory molecules, and specific expression of CD127, CCR7, and PDL1. These cells also possessed the ability to stimulate and re-stimulate T cells and displayed reduced responses to toll-like receptor (TLR) agonists compared to conventional DCs. While expression of AIRE was enriched within CCR7+CD127+ DCs, single-cell RNA sequencing revealed expression of AIRE to be transient, rather than stable, and associated with the differentiation to a mature phenotype. The role of AIRE in central tolerance induction within the thymus is well-established, however our study shows that AIRE expression within the periphery is not associated with an enriched expression of tissue-restricted antigens (TRAs). This unexpected finding, suggestive of wider functions of AIRE, may provide an explanation for the non-autoimmune symptoms of APECED patients who lack functional AIRE.

Keywords: AIRE; PDL1; dendritic cells; maturation; tissue restricted antigen.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • B7-H1 Antigen / metabolism
  • Cell Communication / immunology
  • Cells, Cultured
  • Child, Preschool
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Humans
  • Infant
  • Infant, Newborn
  • Interleukin-7 Receptor alpha Subunit / metabolism
  • Lymphocyte Activation
  • Palatine Tonsil / cytology*
  • Palatine Tonsil / immunology
  • Palatine Tonsil / metabolism
  • Primary Cell Culture
  • Receptors, CCR7 / metabolism
  • T-Lymphocytes / immunology
  • Transcription Factors / immunology
  • Transcription Factors / metabolism*

Substances

  • APECED protein
  • B7-H1 Antigen
  • CCR7 protein, human
  • CD274 protein, human
  • Interleukin-7 Receptor alpha Subunit
  • Receptors, CCR7
  • Transcription Factors