Background/Purpose: Uncontrolled migration of Th17 cells into the skin and joints is a major driver in the pathogenesis of psoriatic arthritis (PsA). Modulation of T cell migration is thus an attractive option in order to reduce inflammation and restore immune tolerance. Th17 cells and regulatory T cells (Treg) both express CCR6, and migrate into the site of inflammation in response to CCL20. Importantly, maintenance of the correct Treg: effector T cell (Teff) ratio via appropriate control of cell migration is critical in the establishment of immune homeostasis. Dysregulation of Teff migration leads to their accumulation within inflamed tissue, and a resultant imbalance in the Treg: Teff ratio at the inflammatory site, thereby perpetuating disease. Here, we investigated the ability of Treg to modulate Th17 migration, in order to understand whether Treg can control Th17 migration in healthy individuals, and whether this axis in perturbed in PsA patients.

Methods:  IL-17 production and association with CCR6 within FoxP3⁺ and FoxP3^– cells was measured in healthy and PsA peripheral blood mononuclear cells (PBMC) and synovial fluid (SF). Modulation of Th17 cell migration by Treg was investigated using a transwell model of CCR6-mediated migration towards CCL20. Sorted CD4⁺Treg (CD25^highCD127^low) were mixed with Cell Trace Violet (CTV)-labelled Teff (CD25^lowCD127^high). The number of CTV⁺Teff migrated towards CCL20 in the presence or absence of Treg was enumerated by FACS using counting beads.

Results: CD4⁺IL-17⁺ cells were significantly increased in the peripheral blood (PB) (p=0.03*) and synovial fluid (SF) (p<0.0001***) of PsA untreated/DMARD patients compared to healthy controls and Adalimumab (Ada) treated PsA patients. We also observed an increase in IL-17 within CD4⁺ FoxP3⁺ synovial fluid Treg compared to HC PBMC (p=0.05*). Overall, the percentage of FoxP3⁺ Treg in PsA untreated/DMARD PBMC was significantly reduced compared to HC PBMC (p=0.007**) and Adalimumab treated PsA patients (p=0.02*). We found a 3-fold increase in the percentage of CCR6⁺ Teff (FoxP3^–) cells within PsA SF compared to paired PsA PBMC (p=0.0026**). There was a small (1.5 fold), but significant (p=0.02*) increase in CCR6⁺ Treg (FoxP3⁺) in PsA SF compared to paired PsA PBMC. Co-culture of healthy Treg with healthy Teff down-regulated CCR6-mediated migration towards CCL20 (p=0.03*) but PsA untreated/DMARD Treg enhanced CCR6 mediated migration of PsA untreated/DMARD Teff (p=0.02*). PsA Treg could down-modulate healthy CCR6 mediated Teff migration, whereas healthy Treg were unable to decrease migration of PsA Teff towards CCL20

Conclusion: These data reveal an accumulation of CCR6⁺Th17 cells within the synovial fluid of PsA patients, potentially due to an enhancement of Th17 migration by Treg. In contrast, healthy Treg suppress Th17 migration towards CCL20. We hypothesise that paradoxically, Treg may drive Th17 migration into the skin and joints in PsA, leading to accumulation of Th17 cells at the site of inflammation and propagation of disease. Modulation of this axis may provide an attractive future therapeutic target for patients with PsA.    

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/th17-migration-into-the-synovial-fluid-of-patients-with-active-psoriatic-arthritis-is-enhanced-by-regulatory-t-cells/