A distinct tolerogenic subset of splenic IDO+CD11b+ dendritic cells from orally tolerized mice is responsible for induction of systemic immune tolerance and suppression of collagen-induced arthritis

In oral tolerance, locally instigated tolerance in the gut propagate to systemic tolerance. In order to investigate the mechanism, we analyzed indoleamine 2,3-dioxygenase (IDO) expression in splenic dendritic cell (DC) subsets and tested whether DCs suppress collagen-induced arthritis (CIA) by inducing regulatory T cells (Tregs). The proportion of IDO-expressing cells was higher in the CD11b+ subset of splenic DCs from orally tolerized CIA mice. These DCs suppressed type II collagen-specific T cell proliferation and promoted Treg induction from CD4+CD25− T cells using transforming growth factor-β. These DCs also increased the expression of cytotoxic T lymphocyte antigen-4 and programmed death-1 on Tregs. When adoptively transferred, spenic IDO-expressing CD11b+ DCs from tolerized animals suppressed the development of arthritis, increased the Treg/Th17 cell ratio, and decreased the production of inflammatory cytokines in the spleen. Taken together, a distinct subset of splenic IDO+CD11b+DCs is responsible for the systemic immune regulation in oral tolerance.

► IDO was highly expressed in the splenic CD11b+ DC subset from tolerized CIA mice. ► IDO-expressing CD11b+ DCs suppressed Ag-specific T cell proliferation. ► IDO-expressing CD11b+ DCs increased Foxp3+ Treg and decreased IL-17+ T cell populations. ► Adoptive transfer of IDO+CD11b+ DCs from tolerized mice suppressed CIA development. ► IDO+CD11b+ DCs are involved in the establishment of systemic unresponsiveness to Ag.