Date: Monday, November 6, 2017
Session Title: T Cell Biology and Targets in Autoimmune Disease Poster I
Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Autoimmune diseases such as RA are driven by an aberrantly activated immune system and an imbalance between pro- and anti-inflammatory cells, resulting in tissue damage and functional disability in patients. In the blood of treatment-naïve early RA patients, especially CCR6+ Th memory cells, including Th17 and Th17.1 cells, are elevated and more activated compared to healthy controls. Therefore, blocking the full pathogenic potential of CCR6+ Th memory cells to restore the immunological balance in RA is an important challenge. The active vitamin D metabolite 1,25(OH)2D3 can inhibit the various pro-inflammatory cytokines produced by CCR6+ Th memory cells. However, whether 1,25(OH)2D3 also change the phenotype and functional properties of these CCR6+ Th memory cells is not fully elucidated and is the objective of this study.
CCR6+ Th memory cells, excluding Tregs, from treatment-naïve early RA patients or healthy controls were sorted and cultured for three days with or without 1,25(OH)2D3 in the presence of anti-CD3 and anti-CD28. After that they were harvested for microarray analysis, RT-PCR, ELISA or flow cytometry. The cultured cells were also used in functional suppression assays, transwell migration assays and exposed to synovial fluid from active RA patients to test phenotype stability.
Microarray analysis of 1,25(OH)2D3-treated CCR6+ Th memory cells from treatment-naïve early RA patients showed that production of pro-inflammatory factors such as IL-17A, IL-17F, IFNg, IL-22, IL-26 and the Th17-related transcription factor RORC is inhibited. In contrast, anti-inflammatory factors such as IL-10 and CTLA4, but not FoxP3, are induced. To address whether these formerly pathogenic cells also have regulatory capacities, we evaluated their capacity to suppress proliferation of autologous CD3+ T cells. Interestingly, the 1,25(OH)2D3-treated CCR6+ Th memory cells were equally capable of suppressing proliferation of CD3+ T cells as classical Tregs. This confirms that the committed CCR6+ Th memory cells can change their phenotype from pro- to anti-inflammatory with regulatory capacity. Furthermore, we found that the shift in phenotype did not affect their potential to migrate towards the site of inflammation, since 1,25(OH)2D3-treated CCR6+ Th memory cells migrated equally well towards synovial fluid in a transwell migration assay compared to control-treated cells. Finally, we addressed the stability of the change in phenotype. When cells have been exposed to 1,25(OH)2D3 for three days, the anti-inflammatory phenotype is maintained for at least 7 days. Importantly, the cells retain this phenotype upon exposure to an inflammatory environment, modeled by synovial fluid.
For the first time we show here that human committed pro-inflammatory CCR6+ Th memory cells can shift towards an anti-inflammatory cell with functional regulatory capacities. Furthermore, these cells can migrate towards synovial inflammation and keep their anti-inflammatory phenotype in this environment. Thereby, these 1,25(OH)2D3 treated CCR6+ Th memory cells can contribute to restoring the immunological balance and inhibiting synovial inflammation in RA.
To cite this abstract in AMA style:Dankers W, Davelaar N, van Hamburg JP, Asmawidjaja P, Wen H, van Leeuwen J, Colin E, Lubberts E. Human C-C Chemokine Receptor-6 (CCR6)+ Th Memory Cells, Including Th17 and Th17.1 Cells, Change into Anti-Inflammatory Cells with Regulatory Capacity upon Exposure to Vitamin D [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/human-c-c-chemokine-receptor-6-ccr6-th-memory-cells-including-th17-and-th17-1-cells-change-into-anti-inflammatory-cells-with-regulatory-capacity-upon-exposure-to-vitamin-d/. Accessed November 27, 2022.
« Back to 2017 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/human-c-c-chemokine-receptor-6-ccr6-th-memory-cells-including-th17-and-th17-1-cells-change-into-anti-inflammatory-cells-with-regulatory-capacity-upon-exposure-to-vitamin-d/