Abstract
BackgroundChronic 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.MethodsTh17/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)2D3. Cultures were analyzed by RT-PCR, ELISA, or flow cytometry.ResultsTh17/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.ConclusionsHuman 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)2D3, is able to suppress CCR6+ memTh subpopulation-driven SF activation.
Highlights
Chronic synovial inflammation is an important hallmark of inflammatory arthritis, but the cells and mechanisms involved are incompletely understood
CCR6+ memory T-helper (memTh) subpopulations differ in cytokine production, but not in expression of RAR Related Orphan Receptor C (RORC), in healthy donors and treatment-naïve rheumatoid arthritis (RA) patients For studying the role and properties of CCR6+ memTh subpopulations, Th17/Th22, Th17.1, double-positive (DP), and double-negative (DN) cells were sorted from healthy Peripheral blood mononuclear cells (PBMC) based on the chemokine receptors CXCR3 and CCR4 (Fig. 1A, Additional file 4)
Th17/Th22 cells showed a trend towards being the strongest producers of IL-17A, IL-22, and Granulocyte-macrophage colonystimulating factor (GM-CSF), whereas Th17.1 and DP cells produced the highest levels of IFNγ (Fig. 1B, upper panel)
Summary
Chronic synovial inflammation is an important hallmark of inflammatory arthritis, but the cells and mechanisms involved are incompletely understood. The relevance of T cell biology in inflammatory arthritis is supported by their infiltration into arthritic joints and by various RA associated genes, including MHC class II genes, PTPN22, CTLA-4, and CCR6, that are related to T cell biology [4,5,6]. Both Th1 and Th17 cells are present in inflammatory arthritis, which of these cell types drives chronicity of joint inflammation is not fully elucidated [7]. With the discovery of the newly identified Th17.1 cells, which express TBX21 and produce IFNγ but are RORC positive, the potential role for IFNγ-producing Th1 cells in arthritis needs to be reconsidered [8, 9]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
