Figure 2. Three non–mutually exclusive possible mechanisms of DC involvement in IBD that lead to an imbalance between Th17/Th1 and Treg cells have been reported.

(A) Involvement of ATP-releasing or flagellated bacteria. An unexpected increase in the number of bacteria releasing ATP or expressing flagellin can lead to the activation of CX3CR1⁺CD70⁺ DCs that favor Th17 cell differentiation (i). (B) Involvement of the local microenvironment. A defect in the release of immunomodulatory factors (e.g., TSLP, TGF-β, and RA) by IECs may lead to a reduction in Treg numbers caused by the failure of conditioning tolerogenic CD103⁺ DCs (ii). Local inflammation may lead to the recruitment of inflammatory DCs; by releasing IL-12 and TNF-α, these inflammatory DCs drive the differentiation of IFN-γ and TNF-α Th1 cells (iii). (C) Involvement of immune cells. Inflammation may also affect the differentiation of tolerogenic macrophages from recruited monocytes, leading to reduction in Treg differentiation and inability to control the activity of CX3CR1⁺CD70⁺ DCs (iv). Th17 or Th1 cells are strongly restimulated in situ by CD70⁺ or OX40L⁺ APCs (v). Both DC types have not been described in humans, but the retention of activated DCs has been shown. The mechanisms in A–C may participate in disease induction by generating an imbalance between Tregs and Th1 or Th17 cells (vi). Th1/Th17 cells release IFN-γ, TNF-α, or IL-17, which contribute to tissue destruction through the release of MMPs by activated fibroblasts and the recruitment of neutrophils. Th1 or inflammatory, DC-derived TNF-α may also increase the endothelial expression of MAdCAM-1, thus favoring the recruitment of α₄β₇⁺ Th1 cells.