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Abstract Number: 1920

Vitamin D Induces a Type 1 Regulatory T Cell (Tr1)-like Phenotype in Human C-C Chemokine Receptor Type 6 (Ccr6)+ th Cells and Promotes Their Migration to an Inflammatory Environment

Wendy Dankers1, Jan Piet van Hamburg1, Nadine Davelaar1, Patrick Asmawidjaja1, Hoyan Wen1, Johannes van Leeuwen2, Edgar Colin3 and Erik Lubberts1, 1Rheumatology and Immunology, Erasmus MC, University Medical Center, Rotterdam, Netherlands, 2Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, Netherlands, 3Rheumatology, ZGT, Almelo, Netherlands

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: Chemokine Receptors, T cells, T-Regulatory Cells, Vitamin D and rheumatoid arthritis (RA)

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Session Information

Date: Monday, November 14, 2016

Session Title: T Cell Biology and Targets in Autoimmune Disease - Poster Session I

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose: The active vitamin D metabolite 1,25(OH)2D3 suppresses various experimental autoimmune diseases. In addition, serum vitamin D levels, vitamin D intake and polymorphisms in the vitamin D receptor (VDR) are associated with disease incidence and severity in human autoimmune diseases such as rheumatoid arthritis (RA). However, the mechanism behind these immunosuppressive effects is currently unknown. Previously we have demonstrated that 1,25(OH)2D3 directly inhibits pathogenicity of CCR6+ T helper (Th) cells. These cells, which include Th17 and Th17.1 cells, are thought to play an important role in the pathogenesis of autoimmune diseases such as rheumatoid arthritis (RA). They produce cytokines like IL-17A and TNFα and activate synovial fibroblasts to induce a pro-inflammatory feedback loop. This interaction may underlie the chronic joint inflammation in RA. Therefore CCR6+ Th cells are an interesting therapeutic target in this disease. Here we further investigated the effect of 1,25(OH)2D3 on CCR6+ Th cells to understand how 1,25(OH)2D3 suppresses the inflammatory responses in autoimmune diseases.

Methods: We cultured CCR6+ Th cells from treatment-naïve early RA patients with or without 1,25(OH)2D3 and generated gene-expression profiles. These profiles were validated using RT-PCR, ELISA and flow cytometry. Functional effects were evaluated via co-culture with RA synovial fibroblasts (RASF) and Boyden chamber-based migration assays.

Results: Gene-expression profiles from CCR6+ Th cells confirmed that 1,25(OH)2D3 treatment downregulated pro-inflammatory cytokines like IL-17A, IL-17F and IL-22, but also genes important for the pathogenic Th17 phenotype like RORC and IL-23R. In contrast, 1,25(OH)2D3 induced the anti-inflammatory cytokine IL-10, but not the classical Treg transcription factor FoxP3. Instead, upregulation of genes like LAG3, c-MAF, CTLA4, and IRF8 suggests the induction of a Tr1-like phenotype. Interestingly, these CCR6+ Th cells cultured with 1,25(OH)2D3 were less capable of inducing the pro-inflammatory loop upon interaction with RASF. This suggests that the modulated CCR6+ Th cells could contribute to regulating synovial inflammation. However, for this they need to be capable of migration towards inflammatory sites. Therefore we investigated the migration of CCR6+ Th cells treated with 1,25(OH)2D3 towards synovial inflammation as modeled by the CCR6+ Th – RASF co-culture. Indeed, the 1,25(OH)2D3-treated CCR6+ Th cells migrate faster towards the site of inflammation than untreated cells.

Conclusion: 1,25(OH)2D3 inhibits the pathogenic Th17 phenotype in CCR6+ Th cells, while inducing a regulatory Tr1-like phenotype. These cells will then migrate towards the site of inflammation, where they are less potent activators of RASF. This effect of 1,25(OH)2D3 on CCR6+ Th cells may underlie the suppression of RA by vitamin D.


Disclosure: W. Dankers, None; J. P. van Hamburg, None; N. Davelaar, None; P. Asmawidjaja, None; H. Wen, None; J. van Leeuwen, None; E. Colin, None; E. Lubberts, None.

To cite this abstract in AMA style:

Dankers W, van Hamburg JP, Davelaar N, Asmawidjaja P, Wen H, van Leeuwen J, Colin E, Lubberts E. Vitamin D Induces a Type 1 Regulatory T Cell (Tr1)-like Phenotype in Human C-C Chemokine Receptor Type 6 (Ccr6)+ th Cells and Promotes Their Migration to an Inflammatory Environment [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/vitamin-d-induces-a-type-1-regulatory-t-cell-tr1-like-phenotype-in-human-c-c-chemokine-receptor-type-6-ccr6-th-cells-and-promotes-their-migration-to-an-inflammatory-environment/. Accessed January 28, 2023.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/vitamin-d-induces-a-type-1-regulatory-t-cell-tr1-like-phenotype-in-human-c-c-chemokine-receptor-type-6-ccr6-th-cells-and-promotes-their-migration-to-an-inflammatory-environment/

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