Tolerogenic DCs. There are a number of pathways by which immature MDCs can be rendered tolerogenic. Some of these mechanisms may overlap. The 5 mechanisms summarized here (from left to right) include antigen presentation by resting (steady-state) DCs; exposure of DCs to “modulating” cytokines such as IL-10 and transforming growth factor-β (TGFβ) or to other modulating substances such as corticosteroids and vitamin D₃; targeted inhibition of the RelB transcription factor (which controls CD40 expression) or direct inhibition of CD40; DC exposure to CD8⁺CD28^– regulatory T (Tr) cells (which have been associated with graft tolerance in patients who received transplants); and the induction of indoleamine 2,3-dioxygenase (IDO)–expressing DCs (IDO-DCs) by ligating B7-1 and B7-2 molecules on the DC with a cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4)–immunoglobulin fusion protein or by CD4⁺CD25⁺ Tr cells. Immature DCs (left) can induce tolerance through the induction of abortive proliferation and anergy, as well as through the induction of IL-10–producing Tr cells.^84,85,86  DCs that have been modulated by factors such as IL-10 or TGFβ (second from left) may also lead to the inhibition of effector T-cell expansion and the induction of IL-10–secreting Tr cells.^87,88  Stat3 signaling within the DC appears to be critical for this effect.⁸⁹  IL-10–producing Tr cells are also induced by DCs that are deficient in RelB or CD40⁹⁰  (center). CD8⁺CD28^– Tr cells induce tolerogenic DCs by up-regulating inhibitory receptors immunoglobulin-like transcript 3 (ILT3) and ILT4 on the DC surface, which ultimately leads to decreased DC expression of B7-1 and B7-2 and T-cell anergy⁹¹  (second from right). Finally, IDO-DCs (right) inhibit T-cell expansion and induce T-cell apoptosis by way of IDO-mediated tryptophan catabolism within the DCs.^92-94  Both MDCs and PDCs can also be rendered tolerogenic by factors secreted by malignant tumors (not shown).⁹⁵