Novel role of plasmacytoid dendritic cells in humans: Induction of interleukin‐10–producing treg cells by plasmacytoid dendritic cells in patients with rheumatoid arthritis responding to therapy

Abstract

Reestablishing immune tolerance and long-term suppression of disease represent major therapeutic goals in rheumatoid arthritis (RA). Dendritic cells (DCs) likely play a central role in such regulation via the expansion and/or induction of Treg cells. The present study was undertaken to explore the contribution of DCs to the development of Treg cells in a human autoimmune disease setting. DC subsets were characterized by flow cytometry in the peripheral blood and synovial fluid of patients with RA. Proliferation of and cytokine release by naive CD4+CD25- T cells were measured in cocultures of these cells with DCs from patients with RA and healthy controls. The suppressive capacity of DC-polarized T cells was explored in vitro by a standard suppression assay. Only very low numbers of both plasmacytoid DCs (CD303+) and myeloid DCs (CD1c+) were present in the peripheral blood of patients with active RA. In contrast, patients with therapy-induced remission of RA exhibited higher numbers of circulating plasmacytoid DCs. Mature plasmacytoid DCs from RA patients with low disease activity, but not those from healthy controls, expressed high levels of indoleamine 2,3-dioxygenase and promoted the differentiation of allogeneic naive CD4+CD25- T cells into interleukin-10-secreting Treg cells, or Tr1 cells, that showed poor proliferation in vitro. Importantly, these plasmacytoid DC-primed Treg cells potently suppressed the proliferation of autologous naive CD4+ T cells, in a dose-dependent manner. These results demonstrate, for the first time, that human plasmacytoid DCs may be educated within the rheumatoid microenvironment to acquire a tolerogenic phenotype. Modulation of the immune response by plasmacytoid DCs might provide novel immune-based therapies in autoimmunity and transplantation.