Synovial T cell hyporesponsiveness to myeloid dendritic cells is reversed by preventing PD-1/PD-L1 interactions

Abstract

IntroductionThe aim of this study was to investigate PD-1/PD-L1 involvement in the hyporesponsiveness of rheumatoid arthritis (RA) synovial fluid (SF) CD4 T cells upon stimulation by thymic stromal lymphopoietin (TSLP)–primed CD1c myeloid dendritic cells (mDCs).MethodsExpression of PD-1 on naïve (Tn), central memory (Tcm) and effector memory (Tem) CD4 T cell subsets was assessed by flow cytometry. PD-L1 expression and its regulation upon TSLP stimulation of mDCs from peripheral blood (PB) and SF of RA patients were investigated by quantitative RT-PCR and flow cytometry. The involvement of PD-1/PD-L1 interactions in SF T cell hyporesponsiveness upon (TSLP-primed) mDC activation was determined by cell culture in the presence of PD-1 blocking antibodies, with or without interleukin 7 (IL-7) as a recognized suppressor of PD-1 expression.ResultsPD-1 expression was increased on CD4 T cells derived from SF compared with PB of RA patients. TSLP increased PD-L1 mRNA expression in both PB and SF mDCs. PD-L1 protein expression was increased on SF mDCs compared with PB mDCs and was associated with T cell hyporesponsiveness. Blockade of PD-1, as well as IL-7 stimulation, during cocultures of memory T cells and (TSLP-primed) mDCs from RA patients significantly recovered T cell proliferation.ConclusionSF T cell hyporesponsiveness upon (TSLP-primed) mDC stimulation in RA joints is partially dependent on PD-1/PD-L1 interactions, as PD-1 and PD-L1 are both highly expressed on SF T cells and mDCs, respectively, and inhibiting PD-1 availability restores T cell proliferation. The potential of IL-7 to robustly reverse this hyporesponsiveness suggests that such proinflammatory cytokines in RA joints strongly contribute to memory T cell activation.

Statins can suppress DC‐mediated Th2 responses through the repression of OX40‐ligand and CCL17 expression

“…Although the highest tested concentration (100 µM) of both statins showed a cytotoxic effect on mDCs, statin concentrations of 1−10 µM did not affect the mDC survival. We next investigated the effect of statins on mDC maturation by measuring the expression of CD40, CD80, CD83, CD86, HLA‐DR, and programmed death ligand 1, known to be induced by the culture with TSLP or TLR‐ligand stimuli . MFI of these markers remained unchanged in the presence of 1−10 µM of pitavastatin or simvastatin (Fig.…”

Dendritic cell recruitment and activation in autoimmunity

“…TSLP priming resulted in PD-L1 upregulation on DCs, which could negatively regulate PD-1-expressing T cells. However, it was shown that the abundance of IL-7 in RA joints plays a critical role in overcoming PD-1-mediated inhibition of T cells, leading to the prevalence of T-activating effects [164,165]. Furthermore, GM-CSF produced by synovial CD4 þ T cells supported the differentiation and activation of infDC, thus promoting a local inflammatory amplification loop [166].…”

Soluble PD-1 aggravates progression of collagen-induced arthritis through Th1 and Th17 pathways

“…PD-L1 is widely expressed in activated endothelial and epithelial cells, and it is therefore thought to be important for the fine-tuning of lymphocyte activation at the level of synovial tissue [ 20 , 21 ]. Increased numbers of PD-1 + and PD-L1 + cells were found in the synovium of patients with active RA [ 22 – 24 ].…”