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

Frederique M Moret, Kim MG van der Wurff-Jacobs, Johannes WJ Bijlsma, Floris PJG Lafeber, Joel AG van Roon

IntroductionThis study aimed to investigate PD-1/PD-L1 involvement in the hypo-responsiveness of rheumatoid arthritis (RA) synovial fluid 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 synovial fluid (SF) of RA patients were investigated by quantitative reverse transcription polymerase chain reaction and flow cytometry. The involvement of PD-1/PD-L1 interactions in SF T cell hypo-responsiveness 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 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 hypo-responsiveness. Blockade of PD-1, as well as IL-7 stimulation, during co-cultures of memory T cells and (TSLP-primed) mDCs from RA patients significantly recovered T cell proliferation.ConclusionSF T cell hypo-responsiveness 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 hypo-responsiveness suggest that such proinflammatory cytokines in RA joints strongly contribute to memory T cell activation.