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The heterogeneous human memory CCR6+ T helper-17 populations differ in T-bet and cytokine expression but all activate synovial fibroblasts in an IFNγ-independent manner
BACKGROUND: Chronic synovial inflammation is an important hallmark of inflammatory arthritis, but the cells and mechanisms involved are incompletely understood. Previously, we have shown that CCR6+ memory T-helper (memTh) cells and synovial fibroblasts (SF) activate each other in a pro-inflammatory...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173960/ https://www.ncbi.nlm.nih.gov/pubmed/34082814 http://dx.doi.org/10.1186/s13075-021-02532-9 |
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author | Dankers, Wendy den Braanker, Hannah Paulissen, Sandra M. J. van Hamburg, Jan Piet Davelaar, Nadine Colin, Edgar M. Lubberts, Erik |
author_facet | Dankers, Wendy den Braanker, Hannah Paulissen, Sandra M. J. van Hamburg, Jan Piet Davelaar, Nadine Colin, Edgar M. Lubberts, Erik |
author_sort | Dankers, Wendy |
collection | PubMed |
description | BACKGROUND: Chronic synovial inflammation is an important hallmark of inflammatory arthritis, but the cells and mechanisms involved are incompletely understood. Previously, we have shown that CCR6+ memory T-helper (memTh) cells and synovial fibroblasts (SF) activate each other in a pro-inflammatory feedforward loop, which potentially drives persistent synovial inflammation in inflammatory arthritis. However, the CCR6+ memTh cells are a heterogeneous population, containing Th17/Th22 and Th17.1 cells. Currently, it is unclear which of these subpopulations drive SF activation and how they should be targeted. In this study, we examined the individual contribution of these CCR6+ memTh subpopulations to SF activation and examined ways to regulate their function. METHODS: Th17/Th22 (CXCR3(−)CCR4(+)), Th17.1 (CXCR3(+)CCR4(−)), DP (CXCR3(+)CCR4(+)), and DN (CXCR3(−)CCR4(−)) CCR6+ memTh, cells sorted from PBMC of healthy donors or treatment-naïve early rheumatoid arthritis (RA) patients, were cocultured with SF from RA patients with or without anti-IL17A, anti-IFNγ, or 1,25(OH)(2)D(3). Cultures were analyzed by RT-PCR, ELISA, or flow cytometry. RESULTS: Th17/Th22, Th17.1, DP, and DN cells equally express RORC but differ in production of TBX21 and cytokines like IL-17A and IFNγ. Despite these differences, all the individual CCR6+ memTh subpopulations, both from healthy individuals and RA patients, were more potent in activating SF than the classical Th1 cells. SF activation was partially inhibited by blocking IL-17A, but not by inhibiting IFNγ or TBX21. However, active vitamin D inhibited the pathogenicity of all subpopulations leading to suppression of SF activation. CONCLUSIONS: Human CCR6+ memTh cells contain several subpopulations that equally express RORC but differ in TBX21, IFNγ, and IL-17A expression. All individual Th17 subpopulations are more potent in activating SF than classical Th1 cells in an IFNγ-independent manner. Furthermore, our data suggest that IL-17A is not dominant in this T cell-SF activation loop but that a multiple T cell cytokine inhibitor, such as 1,25(OH)(2)D(3), is able to suppress CCR6+ memTh subpopulation-driven SF activation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13075-021-02532-9. |
format | Online Article Text |
id | pubmed-8173960 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-81739602021-06-03 The heterogeneous human memory CCR6+ T helper-17 populations differ in T-bet and cytokine expression but all activate synovial fibroblasts in an IFNγ-independent manner Dankers, Wendy den Braanker, Hannah Paulissen, Sandra M. J. van Hamburg, Jan Piet Davelaar, Nadine Colin, Edgar M. Lubberts, Erik Arthritis Res Ther Research Article BACKGROUND: Chronic synovial inflammation is an important hallmark of inflammatory arthritis, but the cells and mechanisms involved are incompletely understood. Previously, we have shown that CCR6+ memory T-helper (memTh) cells and synovial fibroblasts (SF) activate each other in a pro-inflammatory feedforward loop, which potentially drives persistent synovial inflammation in inflammatory arthritis. However, the CCR6+ memTh cells are a heterogeneous population, containing Th17/Th22 and Th17.1 cells. Currently, it is unclear which of these subpopulations drive SF activation and how they should be targeted. In this study, we examined the individual contribution of these CCR6+ memTh subpopulations to SF activation and examined ways to regulate their function. METHODS: Th17/Th22 (CXCR3(−)CCR4(+)), Th17.1 (CXCR3(+)CCR4(−)), DP (CXCR3(+)CCR4(+)), and DN (CXCR3(−)CCR4(−)) CCR6+ memTh, cells sorted from PBMC of healthy donors or treatment-naïve early rheumatoid arthritis (RA) patients, were cocultured with SF from RA patients with or without anti-IL17A, anti-IFNγ, or 1,25(OH)(2)D(3). Cultures were analyzed by RT-PCR, ELISA, or flow cytometry. RESULTS: Th17/Th22, Th17.1, DP, and DN cells equally express RORC but differ in production of TBX21 and cytokines like IL-17A and IFNγ. Despite these differences, all the individual CCR6+ memTh subpopulations, both from healthy individuals and RA patients, were more potent in activating SF than the classical Th1 cells. SF activation was partially inhibited by blocking IL-17A, but not by inhibiting IFNγ or TBX21. However, active vitamin D inhibited the pathogenicity of all subpopulations leading to suppression of SF activation. CONCLUSIONS: Human CCR6+ memTh cells contain several subpopulations that equally express RORC but differ in TBX21, IFNγ, and IL-17A expression. All individual Th17 subpopulations are more potent in activating SF than classical Th1 cells in an IFNγ-independent manner. Furthermore, our data suggest that IL-17A is not dominant in this T cell-SF activation loop but that a multiple T cell cytokine inhibitor, such as 1,25(OH)(2)D(3), is able to suppress CCR6+ memTh subpopulation-driven SF activation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13075-021-02532-9. BioMed Central 2021-06-03 2021 /pmc/articles/PMC8173960/ /pubmed/34082814 http://dx.doi.org/10.1186/s13075-021-02532-9 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Article Dankers, Wendy den Braanker, Hannah Paulissen, Sandra M. J. van Hamburg, Jan Piet Davelaar, Nadine Colin, Edgar M. Lubberts, Erik The heterogeneous human memory CCR6+ T helper-17 populations differ in T-bet and cytokine expression but all activate synovial fibroblasts in an IFNγ-independent manner |
title | The heterogeneous human memory CCR6+ T helper-17 populations differ in T-bet and cytokine expression but all activate synovial fibroblasts in an IFNγ-independent manner |
title_full | The heterogeneous human memory CCR6+ T helper-17 populations differ in T-bet and cytokine expression but all activate synovial fibroblasts in an IFNγ-independent manner |
title_fullStr | The heterogeneous human memory CCR6+ T helper-17 populations differ in T-bet and cytokine expression but all activate synovial fibroblasts in an IFNγ-independent manner |
title_full_unstemmed | The heterogeneous human memory CCR6+ T helper-17 populations differ in T-bet and cytokine expression but all activate synovial fibroblasts in an IFNγ-independent manner |
title_short | The heterogeneous human memory CCR6+ T helper-17 populations differ in T-bet and cytokine expression but all activate synovial fibroblasts in an IFNγ-independent manner |
title_sort | heterogeneous human memory ccr6+ t helper-17 populations differ in t-bet and cytokine expression but all activate synovial fibroblasts in an ifnγ-independent manner |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173960/ https://www.ncbi.nlm.nih.gov/pubmed/34082814 http://dx.doi.org/10.1186/s13075-021-02532-9 |
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