Background/Purpose:

Enrichment of regulatory T cells (Treg) has been reported in the synovial fluid (SF) of RA patients, although they fail to alleviate the joint inflammation. These cells utilize programed death receptor-1 (PD-1) mediated pathway to dampen the effector T cell response.  We hypothesized that deficit in the PD-1 pathway may be responsible for functional incapacitation of locally accumulated Treg cells in RA patients. To understand the cause of the failure of locally enriched Treg cells in controlling synovial inflammation, we investigated the role of PD-1 in modulating the function of the infiltrating T cells. Here, we demonstrate that lack of PD-L1 on synovial machorphages (CD14⁺ cells) incapacitates the Treg cells and engaging PD-L1 can functionally resuscitate the Treg cells and dampens the inflammatory T cells.

Methods:

We isolated mononuclear cells from peripheral blood (PBL) and synovial fluid (SF) 25 active RA patients. Surface expression of PD-1 and its ligand (PD-L1) were seen on Treg cells and macrophages (CD14⁺) by the use of flowcytometry. Anti inflammatory cytokine IL-10, TGF-β in Treg (CD4⁺FoxP3⁺) and proinflammatory cytokines IFN-γ, IL-17A, TNF-α in effector T cells (CD4⁺) were measured with FACS based intracellular staining after treatment with PD-L1 Fusion chimeric protein (PD-L1 Fc) in presence of TCR engagement. 

Results: Our result shows that synovial Treg cells are compromised in their IL-10, TGF-β production in-spite of local enrichment of PD-1⁺ Treg (CD4⁺FOXP3⁺) cells. Engaging PD-1 with PD-L1 Fc, IL-10 & TGF-β production by Treg cells. Interestingly, this was accompanied by simultaneous decrease in the frequency of synovial IFN-γ⁺, TNF-α⁺, IL-17A⁺ effector T cells and their proliferation. Moreover, blocking IL-10, TGF-β with specific antibody in similar condition(s) failed to suppress the infiltrating T cells of synovial fluid. This suggests, that deficit of PD-1 mediated suppressive pathway incapacitates the locally accumulated Treg cells. 

Conclusion:

Our results indicate that deficit of PD-1 mediated suppressive pathway incapacitates the locally accumulated Treg cells and engaging PD-1 may restore the suppressive function of synovial Treg cells via IL-10, TGF-β production. Rejuvenating synovial Treg cells may be used to ameliorate the joint inflammation in rheumatoid arthritis. 

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/engaging-pd-1-resuscitates-synovial-treg-cells-and-dampens-the-joint-infiltrating-t-cells-in-rheumatoid-arthritis/