Maturing Human CD127+ CCR7+ PDL1+ Dendritic Cells Express AIRE in the Absence of Tissue Restricted Antigens
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)...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-01-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2018.02902/full |
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| author | Joannah R. Fergusson Michael D. Morgan Melanie Bruchard Leonie Huitema Leonie Huitema Balthasar A. Heesters Vincent van Unen Jan Piet van Hamburg Jan Piet van Hamburg Nicole N. van der Wel Daisy Picavet Frits Koning Sander W. Tas Sander W. Tas Mark S. Anderson John C. Marioni John C. Marioni John C. Marioni Georg A. Holländer Hergen Spits |
| author_facet | Joannah R. Fergusson Michael D. Morgan Melanie Bruchard Leonie Huitema Leonie Huitema Balthasar A. Heesters Vincent van Unen Jan Piet van Hamburg Jan Piet van Hamburg Nicole N. van der Wel Daisy Picavet Frits Koning Sander W. Tas Sander W. Tas Mark S. Anderson John C. Marioni John C. Marioni John C. Marioni Georg A. Holländer Hergen Spits |
| author_sort | Joannah R. Fergusson |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T07:53:55Z |
| format | Article |
| id | doaj.art-5a82ce720c14415a91015c3f54818c7a |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-11T07:53:55Z |
| publishDate | 2019-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-5a82ce720c14415a91015c3f54818c7a2022-12-22T01:15:15ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-01-01910.3389/fimmu.2018.02902414523Maturing Human CD127+ CCR7+ PDL1+ Dendritic Cells Express AIRE in the Absence of Tissue Restricted AntigensJoannah R. Fergusson0Michael D. Morgan1Melanie Bruchard2Leonie Huitema3Leonie Huitema4Balthasar A. Heesters5Vincent van Unen6Jan Piet van Hamburg7Jan Piet van Hamburg8Nicole N. van der Wel9Daisy Picavet10Frits Koning11Sander W. Tas12Sander W. Tas13Mark S. Anderson14John C. Marioni15John C. Marioni16John C. Marioni17Georg A. Holländer18Hergen Spits19Department of Experimental Immunology, Academic Medical Center, Amsterdam, NetherlandsWellcome Sanger Institute, Hinxton, United KingdomDepartment of Experimental Immunology, Academic Medical Center, Amsterdam, NetherlandsDepartment of Rheumatology & Clinical Immunology and Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, University of Amsterdam, Amsterdam, NetherlandsAmsterdam Rheumatology & immunology Center (ARC), Academic Medical Center, Amsterdam, NetherlandsDepartment of Experimental Immunology, Academic Medical Center, Amsterdam, NetherlandsLeiden University Medical Center, Leiden, NetherlandsDepartment of Rheumatology & Clinical Immunology and Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, University of Amsterdam, Amsterdam, NetherlandsAmsterdam Rheumatology & immunology Center (ARC), Academic Medical Center, Amsterdam, NetherlandsEMCA, Medical Biology, Academic Medical Center, Amsterdam, NetherlandsEMCA, Medical Biology, Academic Medical Center, Amsterdam, NetherlandsLeiden University Medical Center, Leiden, NetherlandsDepartment of Rheumatology & Clinical Immunology and Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, University of Amsterdam, Amsterdam, NetherlandsAmsterdam Rheumatology & immunology Center (ARC), Academic Medical Center, Amsterdam, NetherlandsUCSF Diabetes Center, University of California, San Francisco, San Francisco, CA, United StatesWellcome Sanger Institute, Hinxton, United KingdomEuropean Molecular Biology Laboratory - European Bioinformatics Institute (EMBL-EBI), Hinxton, United KingdomCancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom0Laboratory of Developmental Immunology, Weatherall Institute of Molecular Medicine and Department of Paediatrics, University of Oxford, Oxford, United KingdomDepartment of Experimental Immunology, Academic Medical Center, Amsterdam, NetherlandsExpression 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.https://www.frontiersin.org/article/10.3389/fimmu.2018.02902/fulldendritic cellsAIREPDL1maturationtissue restricted antigen |
| spellingShingle | Joannah R. Fergusson Michael D. Morgan Melanie Bruchard Leonie Huitema Leonie Huitema Balthasar A. Heesters Vincent van Unen Jan Piet van Hamburg Jan Piet van Hamburg Nicole N. van der Wel Daisy Picavet Frits Koning Sander W. Tas Sander W. Tas Mark S. Anderson John C. Marioni John C. Marioni John C. Marioni Georg A. Holländer Hergen Spits Maturing Human CD127+ CCR7+ PDL1+ Dendritic Cells Express AIRE in the Absence of Tissue Restricted Antigens Frontiers in Immunology dendritic cells AIRE PDL1 maturation tissue restricted antigen |
| title | Maturing Human CD127+ CCR7+ PDL1+ Dendritic Cells Express AIRE in the Absence of Tissue Restricted Antigens |
| title_full | Maturing Human CD127+ CCR7+ PDL1+ Dendritic Cells Express AIRE in the Absence of Tissue Restricted Antigens |
| title_fullStr | Maturing Human CD127+ CCR7+ PDL1+ Dendritic Cells Express AIRE in the Absence of Tissue Restricted Antigens |
| title_full_unstemmed | Maturing Human CD127+ CCR7+ PDL1+ Dendritic Cells Express AIRE in the Absence of Tissue Restricted Antigens |
| title_short | Maturing Human CD127+ CCR7+ PDL1+ Dendritic Cells Express AIRE in the Absence of Tissue Restricted Antigens |
| title_sort | maturing human cd127 ccr7 pdl1 dendritic cells express aire in the absence of tissue restricted antigens |
| topic | dendritic cells AIRE PDL1 maturation tissue restricted antigen |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2018.02902/full |
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