title: Synovial T cell hyporesponsiveness to myeloid dendritic cells is reversed by preventing PD-1/PD-L1 interactions.
abstract: BACKGROUND
  The 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).
  
  
  METHODS
  Expression 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.
  
  
  RESULTS
  PD-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.
  
  
  CONCLUSIONS
  SF 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.
authors.forename: Frederique M
authors.initials: FM
authors.lastname: Moret
authors.forename: Kim M G
authors.initials: KM
authors.lastname: van der Wurff-Jacobs
authors.forename: Johannes W J
authors.initials: JW
authors.lastname: Bijlsma
authors.forename: Floris P J G
authors.initials: FP
authors.lastname: Lafeber
authors.forename: Joel A G
authors.initials: JA
authors.lastname: van Roon
mesh_terms: D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology; D060890:B7-H1 Antigen / Q000096:biosynthesis*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D061026:Programmed Cell Death 1 Receptor / Q000096:biosynthesis*; D011485:Protein Binding / Q000502:physiology; D013582:Synovial Fluid / Q000166:cytology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism*
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor