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
| Autor: | Hannah den Braanker, Jan Piet van Hamburg, Wendy Dankers, Erik Lubberts, Nadine Davelaar, Sandra M. J. Paulissen, E. M. Colin |
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| Přispěvatelé: | Clinical Immunology and Rheumatology, AII - Inflammatory diseases, Rheumatology, Immunology, Internal Medicine |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Receptors CCR6 Inflammatory arthritis medicine.medical_treatment T cell T cells Inflammation chemical and pharmacologic phenomena Diseases of the musculoskeletal system C-C chemokine receptor type 6 CXCR3 Flow cytometry 03 medical and health sciences 0302 clinical medicine SDG 3 - Good Health and Well-being RAR-related orphan receptor gamma medicine Transcription factors Humans Vitamin D Synovial fibroblasts 030203 arthritis & rheumatology medicine.diagnostic_test Chemistry hemic and immune systems Fibroblasts medicine.disease Molecular biology 030104 developmental biology Cytokine medicine.anatomical_structure RC925-935 Leukocytes Mononuclear Th17 Cells Cytokines Th17.1 Th17 medicine.symptom Research Article |
| Zdroj: | Arthritis Research & Therapy Arthritis Research & Therapy, Vol 23, Iss 1, Pp 1-14 (2021) Arthritis research & therapy, 23(1):157. BioMed Central Arthritis Research and Therapy, 23(1):157. BioMed Central Ltd. |
| ISSN: | 1478-6354 |
| Popis: | 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)2D3. 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)2D3, is able to suppress CCR6+ memTh subpopulation-driven SF activation. |
| Databáze: | OpenAIRE |
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