Background and objectives CCR6+ T-helper (Th) cells and their pro-inflammatory cytokines, including IL-17A, are implicated in the pathogenesis of rheumatoid arthritis (RA). However, within CCR6+ Th cells various subpopulations are present and their clinical relevance in RA is unclear. Therefore, we characterised CCR6+ Th subpopulations with regard to pathogenic potential and disease-modifying antirheumatic drugs (DMARDs) and glucocorticoid (GC) therapy outcome in RA.
Material and methods Within total CCR6+ Th cells from patients with RA, CCR4+CXCR3- (Th17), CCR4-CXCR3+ (Th17.1), CCR4/CXCR3 double-positive (DP) and double-negative (DN) cells were distinguished and/or sorted by flow cytometry. These subpopulations were: analysed for Th17/Th1-associated factors; co-cultured with RA-derived synovial fibroblasts (RASF); related to disease-modifying antirheumatic drugs (DMARDs) and glucocorticoid (GC) therapy response; analysed regarding the expression of multidrug transporters MDR1 and MRP1 and drug efflux potential.
Results All these populations expressed the transcription factor RORC and were present in RA peripheral blood and synovial fluid. Despite differential IL-17A, IL-17F, IFNg and TBX21 expression, all subpopulations, including the IL-17A low-producing Th17.1, DP and DN cells, showed pathogenic activity in the induction of IL-1β, IL-6, IL-8, COX-2 and MMP-3 expression by synovial fibroblasts. MDR1 (ABCB1) and MRP1 (ABCC1) are cellular efflux transporters of glucocorticoids and the DMARD methotrexate. In particular Th17.1 and DN cells expressed relatively high levels of MDR1, whereas MRP1 was expressed at similar levels among the subpopulations. Interestingly, increased drug efflux potential by CCR6+ Th cells, as measured by rhodamine123 and calcein transport, was associated with the lack of DMARD/GC therapy response.
Conclusions Therefore, we conclude that in addition to IL-17-high Th17 cells, IL-17-low CCR6+ Th cells display pathogenic activity in the context of RA. Moreover, we identified efflux transporter expression and efflux activity by RA CCR6+ Th cells. These findings suggest that pathogenic and multidrug resistant CCR6+ Th cells are associated with the lack of DMARD/GC therapy response in patients with RA.
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