Abstract
IntroductionMyeloid dendritic cells (mDCs) are potent T cell-activating antigen-presenting cells that have been suggested to play a crucial role in the regulation of immune responses in many disease states, including rheumatoid arthritis (RA). Despite this, studies that have reported on the capacity of naturally occurring circulating mDCs to regulate T cell activation in RA are still lacking. This study aimed to evaluate the phenotypic and functional properties of naturally occurring CD1c (BDCA-1)+ mDCs from synovial fluid (SF) compared to those from peripheral blood (PB) of RA patients.MethodsCD1c+ mDC numbers and expression of costimulatory molecules were assessed by fluorescence-activated cell sorting (FACS) analysis in SF and PB from RA patients. Ex vivo secretion of 45 inflammatory mediators by mDCs from SF and PB of RA patients was determined by multiplex immunoassay. The capacity of mDCs from SF to activate autologous CD4+ T cells was measured.ResultsCD1c+ mDC numbers were significantly increased in SF versus PB of RA patients (mean 4.7% vs. 0.6%). mDCs from SF showed increased expression of antigen-presenting (human leukocyte antigen (HLA) class II, CD1c) and costimulatory molecules (CD80, CD86 and CD40). Numerous cytokines were equally abundantly produced by mDCs from both PB and SF (including IL-12, IL-23, IL-13, IL-21). SF mDCs secreted higher levels of interferon γ-inducible protein-10 (IP-10), monokine induced by interferon γ (MIG) and, thymus and activation-regulated chemokine (TARC), but lower macrophage-derived chemokine (MDC) levels compared to mDCs from PB. mDCs from SF displayed a strongly increased capacity to induce proliferation of CD4+ T cells associated with a strongly augmented IFNγ, IL-17, and IL-4 production.ConclusionsThis study suggests that increased numbers of CD1c+ mDCs in SF are involved in the inflammatory cascade intra-articularly by the secretion of specific T cell-attracting chemokines and the activation of self-reactive T cells.
Highlights
Myeloid dendritic cells are potent T cell-activating antigen-presenting cells that have been suggested to play a crucial role in the regulation of immune responses in many disease states, including rheumatoid arthritis (RA)
CD1c+ Myeloid dendritic cell (mDC) have an increased frequency and activated phenotype in RA synovial fluid mDCs were characterised by the expression of CD1c and the absence of CD19 in mononuclear cell (MNC) fractions of paired peripheral blood (PB) and SF samples (n = 10) of RA patients
0.2 isotype abundant amounts of T cell-differentiating cytokines as well as increased levels of several inflammatory mediators compared with mDCs from PB, we investigated the capacity of PB-derived and SF-derived mDCs (n = 11 and n = 5, respectively) to activate autologous CD4+ T cells
Summary
Myeloid dendritic cells (mDCs) are potent T cell-activating antigen-presenting cells that have been suggested to play a crucial role in the regulation of immune responses in many disease states, including rheumatoid arthritis (RA). Studies that have reported on the capacity of naturally occurring circulating mDCs to regulate T cell activation in RA are still lacking. DCs instruct T cells to develop a proper immune response by uptake and presentation of antigens and the provision of costimulatory signals and cytokines. External agents to DCs such as cytokines, tissue-derived factors, pathogen-derived antigens and organic molecules may alter the balance between tolerogenic and immunogenic activity of DCs and induce autoimmune disease [7,8]
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