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Front. Immunol. | doi: 10.3389/fimmu.2018.02902

Maturing human CD127+ CCR7+ PDL1+ dendritic cells express AIRE in the absence of tissue restricted antigens

 Joannah R. Fergusson1*,  Michael Morgan2,  Melanie Bruchard1, Leonie Huitema1, Vincent van Uden3, Jan-Piet van Hamburg1, Nicole van der Wel1, Daisy Picavet1,  Sander Tas1,  Frits Koning3, Mark Anderson4,  John Marioni2, Georg Hollander5 and  Hergen Spits1
  • 1Academic Medical Center (AMC), Netherlands
  • 2Wellcome Trust Sanger Institute (WT), United Kingdom
  • 3Leiden University Medical Center, Netherlands
  • 4University of California, San Francisco, United States
  • 5University of Oxford, United Kingdom

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 analysed 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: Dendritic Cells, AIRE, PDL1, maturation, tissue restricted antigen

Received: 17 Jul 2018; Accepted: 27 Nov 2018.

Edited by:

Giovanna Schiavoni, Istituto Superiore di Sanità (ISS), Italy

Reviewed by:

Mitsuru Matsumoto, Tokushima University, Japan
Francesca Granucci, Università degli studi di Milano Bicocca, Italy  

Copyright: © 2018 Fergusson, Morgan, Bruchard, Huitema, van Uden, van Hamburg, van der Wel, Picavet, Tas, Koning, Anderson, Marioni, Hollander and Spits. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Joannah R. Fergusson, Academic Medical Center (AMC), Amsterdam, Netherlands,