Background/Purpose: T cells play a central role in the early stages of rheumatoid arthritis (RA). In this context, we have shown increased proportions of memory CCR6+ Th cells in the blood of treatment naïve patients with early RA compared to healthy individuals. These cells express high levels of IL-17A and are TNFalpha positive. In addition, these memory CCR6+ Th cells induced a proinflammatory loop when co-cultured with RA synovial fibroblasts. This interaction may underlie the development of chronic synovitis. Since the memory CCR6+ T cell populations is a heterogeneous population consisting of e.g. Th17, Th17/Th1, and Th17.1 subpopulations we examined the presence and pathogenic potential of these subpopulations from the blood of treatment naïve patients with early RA.

Methods:   Memory CCR6+ Th cell subpopulations from the blood of treatment naive patients with early RA were distinguished based on chemokine receptor expression. Within these populations, cytokine and transcription factor expression were examined. In addition, CCR6+ subpopulations were sorted by FACS from peripheral blood of treatment naïve patients with early RA and analyzed for their pathologic potential in a co-culture system with RA derived synovial fibroblasts (RASF).

Results:   Based on the expression of CXCR3 and CCR4 four memory CCR6+ Th cell subpopulations were distinguished: Th17, Th17/Th1, Th17.1, and double negative (DN) cells. All four CCR6+ subpopulations expressed RORC, but differ in IL-17A, IL-17F, IL-22, IFNgamma, and T-bet expression. Furthermore, all four subpopulations showed increased pathological potential in co-culture with RASF compared to naive and the classical Th1 cells. Interestingly, even Th17.1, the subpopulation with the lowest IL-17A expression, displayed high pathological potential as shown by stimulating IL-1β, IL-6, IL-8, COX-2 and MMP-3 expression upon co-culture with RASF.

Conclusion:   The memory CCR6+ Th subpopulations differ in IL-17A, IFNgamma and T-bet expression However, all subpopulations express RORC. Interestingly, all subpopulations possess strong pathological potential in stimulating RASF to induce expression of proinflammatory cytokines and MMPs. These findings indicate that in addition to Th17 cells, also other CCR6+ Th subpopulations play a prominent role in the pathogenesis of synovial inflammation despite low IL-17A. Further insight in the molecular phenotype of these subpopulations is warranted to optimize targeted therapy in RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/rorc-positive-th17-th17th1-and-th17-1-cells-from-the-blood-of-treatment-naive-ra-patients-differ-in-il-17a-but-are-all-pathogenic-when-co-cultured-with-ra-synovial-fibroblasts/