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

• Published in: Arthritis research & therapy Vol. 16; no. 6; p. 497
• Main Authors: Moret, Frederique M, van der Wurff-Jacobs, Kim M G, Bijlsma, Johannes W J, Lafeber, Floris P J G, van Roon, Joel A G
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 30.11.2014; BioMed Central
• Subjects: Arthritis; Arthritis, Rheumatoid - metabolism; Arthritis, Rheumatoid - pathology; B7-H1 Antigen - biosynthesis; Cells, Cultured; Dendritic Cells - metabolism; Development and progression; Female; Humans; Interleukins; Male; Medical research; Medicine, Experimental; Physiological aspects; Programmed Cell Death 1 Receptor - biosynthesis; Protein Binding - physiology; Synovial Fluid - cytology; Synovial Fluid - metabolism; T-Lymphocytes - metabolism
• ISSN: 1478-6354; 1478-6362; 1478-6354
• DOI: 10.1186/s13075-014-0497-x

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). 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. 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. 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.