Tolerogenic Splenic IDO⁺Dendritic Cells from the Mice Treated with Induced-Treg Cells Suppress Collagen-Induced Arthritis

Abstract

TGF-β-induced regulatory T cells (iTregs) retain Foxp3 expression and immune-suppressive activity in collagen-induced arthritis (CIA). However, the mechanisms whereby transferred iTregs suppress immune responses, particularly the interplay between iTregs and dendritic cells (DCs) in vivo, remain incompletely understood. In this study, we found that after treatment with iTregs, splenic CD11c+DCs, termed “DCiTreg,” expressed tolerogenic phenotypes, secreted high levels of IL-10, TGF-β, and IDO, and showed potent immunosuppressive activity in vitro. After reinfusion with DCiTreg, marked antiarthritic activity improved clinical scores and histological end-points were observed. The serological levels of inflammatory cytokines and anti-CII antibodies were low and TGF-β production was high in the DCiTreg-treated group. DCiTreg also induced new iTregs in vivo. Moreover, the inhibitory activity of DCiTreg on CIA was lost following pretreatment with the inhibitor of indoleamine 2,3-dioxygenase (IDO). Collectively, these findings suggest that transferred iTregs could induce tolerogenic characteristics in splenic DCs and these cells could effectively dampen CIA in an IDO-dependent manner. Thus, the potential therapeutic effects of iTregs in CIA are likely maintained through the generation of tolerogenic DCs in vivo.

CD11b regulates the Treg/Th17 balance in murine arthritis via IL‐6

“…Previous studies demonstrated the potential of CD11b + DCs to ameliorate CIA . We therefore, examined the potential of a newly produced CD11b + DC line to exert an immune regulatory effect in vivo.…”

Blocking Indolamine-2,3-Dioxygenase Rebound Immune Suppression Boosts Antitumor Effects of Radio-Immunotherapy in Murine Models and Spontaneous Canine Malignancies

“…At baseline, intratumoral TAMs were M2 polarized as assessed by arginase to inducible nitric oxide ratio (data not shown). We next examined the expression of TGF-beta which both induces and is produced by Tregs and TAMs (reviewed in (33, 34)), is produced by IDO expressing dendritic cells (35) and is also known to block lymphocyte activation (36). All of the therapies reduced TGF-beta expression relative to control but this was most pronounced and most significant in the triple combination (Figure 4C, p<0.0001).…”

“…IDO expression has been linked to a tolerogenic DC phenotype, associated with decreased expression of CD80 and MHC II and increased TGF-beta production (35). No change in DC numbers or activation within dLNs was observed (data not shown).…”

IDO-orchestrated crosstalk between pDCs and Tregs inhibits autoimmunity

“…Upon inflammation, IDO production has been shown to compromise T cell proliferation, promote T cell anergy and Tregs [24], [25], [26]. Depending on the experimental context, IDO can be induced either by IFN-γ, IFN-α/β, or TGF-β.…”