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

Joannah R. Fergusson, Michael D. Morgan, Melanie Bruchard, Leonie Huitema, Balthasar A. Heesters, Vincent van Unen, Jan Piet van Hamburg, Nicole N. van der Wel, Daisy Picavet, Frits Koning, Sander W. Tas, Mark S. Anderson, John C. Marioni, Georg A. Holländer, Hergen Spits

Research output: Contribution to journalArticleAcademicpeer-review

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 “extrathymic 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.
Original languageEnglish
JournalFrontiers in Immunology
Volume10
Issue numberJAN
DOIs
Publication statusPublished - 1 Jan 2019
Externally publishedYes

Cite this

Fergusson, J. R., Morgan, M. D., Bruchard, M., Huitema, L., Heesters, B. A., van Unen, V., ... Spits, H. (2019). Maturing human CD127+ CCR7+ PDL1+ dendritic cells express AIRE in the absence of tissue restricted antigens. Frontiers in Immunology, 10(JAN). https://doi.org/10.3389/fimmu.2018.02902
Fergusson, Joannah R. ; Morgan, Michael D. ; Bruchard, Melanie ; Huitema, Leonie ; Heesters, Balthasar A. ; van Unen, Vincent ; van Hamburg, Jan Piet ; van der Wel, Nicole N. ; Picavet, Daisy ; Koning, Frits ; Tas, Sander W. ; Anderson, Mark S. ; Marioni, John C. ; Holländer, Georg A. ; Spits, Hergen. / Maturing human CD127+ CCR7+ PDL1+ dendritic cells express AIRE in the absence of tissue restricted antigens. In: Frontiers in Immunology. 2019 ; Vol. 10, No. JAN.
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title = "Maturing human CD127+ CCR7+ PDL1+ dendritic cells express AIRE in the absence of tissue restricted antigens",
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 “extrathymic 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.",
author = "Fergusson, {Joannah R.} and Morgan, {Michael D.} and Melanie Bruchard and Leonie Huitema and Heesters, {Balthasar A.} and {van Unen}, Vincent and {van Hamburg}, {Jan Piet} and {van der Wel}, {Nicole N.} and Daisy Picavet and Frits Koning and Tas, {Sander W.} and Anderson, {Mark S.} and Marioni, {John C.} and Holl{\"a}nder, {Georg A.} and Hergen Spits",
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Fergusson, JR, Morgan, MD, Bruchard, M, Huitema, L, Heesters, BA, van Unen, V, van Hamburg, JP, van der Wel, NN, Picavet, D, Koning, F, Tas, SW, Anderson, MS, Marioni, JC, Holländer, GA & Spits, H 2019, 'Maturing human CD127+ CCR7+ PDL1+ dendritic cells express AIRE in the absence of tissue restricted antigens' Frontiers in Immunology, vol. 10, no. JAN. https://doi.org/10.3389/fimmu.2018.02902

Maturing human CD127+ CCR7+ PDL1+ dendritic cells express AIRE in the absence of tissue restricted antigens. / Fergusson, Joannah R.; Morgan, Michael D.; Bruchard, Melanie; Huitema, Leonie; Heesters, Balthasar A.; van Unen, Vincent; van Hamburg, Jan Piet; van der Wel, Nicole N.; Picavet, Daisy; Koning, Frits; Tas, Sander W.; Anderson, Mark S.; Marioni, John C.; Holländer, Georg A.; Spits, Hergen.

In: Frontiers in Immunology, Vol. 10, No. JAN, 01.01.2019.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - Maturing human CD127+ CCR7+ PDL1+ dendritic cells express AIRE in the absence of tissue restricted antigens

AU - Fergusson, Joannah R.

AU - Morgan, Michael D.

AU - Bruchard, Melanie

AU - Huitema, Leonie

AU - Heesters, Balthasar A.

AU - van Unen, Vincent

AU - van Hamburg, Jan Piet

AU - van der Wel, Nicole N.

AU - Picavet, Daisy

AU - Koning, Frits

AU - Tas, Sander W.

AU - Anderson, Mark S.

AU - Marioni, John C.

AU - Holländer, Georg A.

AU - Spits, Hergen

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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 “extrathymic 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.

AB - 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 “extrathymic 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.

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