Background/Purpose

As well known, Foxp3+ regulatory T cells play a crucial role in maintaining immune tolerance. It was reported that TGF-β-induced Tregs (iTregs) could retain Foxp3 expression and immune suppressive activity in the collagen-induced arthritis (CIA). However, the mechanisms whereby transferred iTregs suppressed immune response, especially the interplay between iTregs and DCs in vivo, remained incompletely understood. In this study, whether splenic DCs were involved in iTreg-based suppression and how these DCs further inhibited CIA were determined.

Methods

In vitro, iTregs were induced by TGF-β and adoptive transferred into established CIA mice. After 7 days, splenic CD11c⁺DCs were isolated, termed ‘DC_iTreg’. The phenotype, the expression of cytokines and function-associated molecules, the immunogenicity and the suppression on CD4/CD8 T cell differentiation of DC_iTreg were assessed. To determine the suppression in vivo, 5×10⁵ of DC_iTreg were re-infused into the new CIA mice. Clinical and histopathologic scores, cytokine and anti-CII antibody secretion in serum were analyzed. And it also was determined the expression of Foxp3 and function of Tregs after IDO⁺DCs transferred. Additionally, the role of IDO in the inhibitory effect of DC_iTreg was determined by 1-MT blocking in vitroand in CIA mice.

Results After iTregs adoptive transferred, isolated DC_iTreg exhibited a series of tolerogenic characteristics. Compared with splenic DCs isolated from CIA mice (DC_CIA), DC_iTreg expressed obviously lower levels of MHC molecule (IA-IE) and co-stimulatory molecules (CD80, CD86 and CD40). And IL-12p40 and IL-6 production by DC_iTreg were negligible, while high levels of IL-10 and TGF-β were expressed; especially enhanced level of IDO by DC_iTreg was detected, and CD11b⁺DCs were found as a major contributor of IDO expression in iTreg-treated CIA mice. In the proliferation assay, DC_iTreg showed the poor ability to expand effector T cells and had the effective inhibitory potency. Meanwhile, after CD11b⁺IDO⁺DC_iTreg re-infused, a remarkable anti-arthritic activity, improved clinical scores and histological end-points were found. Also, serological levels of TNF-α, IL-6, IL-17 and anti-CII antibodies showed significantly low and TGF-β production was high in the DC_iTreg-treated group. Conversely, DC_CIA could not suppress CIA completely. And IDO⁺DCs could induce the generation and proliferation of functional Foxp3⁺Tregs in vitro and in CIA mice. Moreover, DC_iTreglost the inhibitory ability on CIA when they pretreated 1-MT.

Conclusion

These findings suggested that iTregs could inhibit CIA via tolerogenic splenic DCs formation. These tolerogenic splenic DCs could further effectively dampen the severity and progression of CIA in the IDO-dependent manner, which was associated with modulation of inflammatory cytokine and anti-CII antibody secretion and induction of new iTregs. Thus, the potential therapeutic effect of iTreg in CIA and RA is likely to be maintained, even enlarged by their effects on DCs in vivo.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/tolerogenic-splenic-ido-dendritic-cells-from-the-mice-treated-with-induced-treg-cells-could-suppress-collagen-induced-arthritis/