Two general mechanisms have been proposed by which DCs might maintain peripheral tolerance. The first is that a subtype of specialized regulatory DCs is involved.

The second is that all DCs have a capacity for initiating tolerance or immunity, the distinction depending on the maturation or activation state of DC.

Immature DCs tend to produce T-cell anergy and overall tolerance. The iDCs might induce tolerance by killing T cells, by paralysing them (anergy) or, particularly, by inducing the generation of regulatory T cells. Subsets of murine DC, particularly CD8+ DC, have been implicated in the maintenance of peripheral tolerance, either by stimulating the deletion of activated T cells or by the induction of Tr cells. 

Recent evidence suggests that in the steady state immature DCs present self-antigen to T cells. The lack of co-stimulatory molecules on these cells results in T cell anergy followed, upon subsequent stimulation, by T cell deletion. In addition, dying cells are captured by DCs and, in the absence of inflammatory cytokines, fail to upregulate co-stimulatory molecules, and therefore silence T cells by the deletion or expansion of regulatory T cells. This may be a mechanism that HIV uses to exploit the immune system. HIV antigens presented to T cells by DCs lacking co-stimulatory  molecules may elicit anergy or tolerance rather than immunity. Moreover, DCs in contact with tumour cells, usually express low levels of co-stimulatory molecules. 

The largest source of foreign, nonthreatening antigens is the gut. The gut associated immune response is biased in favor of noninflammatory and inhibitory mechanisms. DCs in the gut still gather information form multiple inputs in conjunction with antigen, but in many cases the outcome is nonstimulatory or induces responses that do not cause harmful inflammation.

Migration cues for tolerogenic DC subsets may be different than those to raditional stimulatory DC.

It has been proposed that DC recruitment and activation is a central control mechanism that discriminates between effective T cell priming and tolerance. The recruitment of immature DC into tissues and theri maturation and migration to draining lymph noces can occur at different rates. In the presence of pathogens, a large number of immature DC will continuosuly enter the tissue, will be activated to a highly stimulatory state adn will migrate to the draining lymph node, resulting in a strong stimulation of T cells. There is evidence that the prcess of DC migraiton can also occur at a lower rate in the absecne of inflammation. This stimulation, however, results in tolerance rather than priming. Because of its central role in T cell priming, DC migration represents an ideal target for escape or immunomodulation. While most viruses induce DC maturation, herpes virus fails to do so and actually inhibits upregulation of CCR7, possibly preventing DC migration to the draining lymph nodes. It is possible that other pathogen as well as tumor cells may use the same strategy to decrease the efficienty of antigen presentation.

Quiescent/Semimature DCs are DCs typically found in the lymphoid tissues of uninfected laboratory mice and are sufficiently mature to express moderate surface levels of MHC II and co-stimulatory molecules, but they are not yet fully activated and maintain some potential for antigen uptake processing. One emerging model is that quiescent DCs that bear self-components are required for the continuous mainteance of self-tolerance, whereas immune responses only occur when invading pathogens provide danger signals to trigger DC activation. Activatied DCs are fully mature and express high surface levels of MHCII and co-stimulatory molecules.

The characteristics of tolerance inducing cells have also been referred to as “semimature DC.” In the steady state, LC present in skin draining LN express low levels of maturation markers such as 2A1, CD86 and CD40 and high leverls of MHCII as well as CD11c.

DCs under steady state will not induce an inflammatory immune response. Although they are able to viorously stimulate T cell proliferation, these proliferated T cells are unresponsive to further stimulation and are eliminated a few days later, most likley due to lack of costimulatory signals.

Mechanisms Accounting for Induction of DCs with Tolerogenic Properties

Immunoglobulin-like transcripts ( ILT): ILT family members posess a long cytoplasmic tail containing immunoreceptor tyrosine-based activatory (ILT1) or inhibitory (IL2-ILT10) motifs. Immunoglobuline-like transcripts (ILT) family members can have activating or inhibitory properties depending on the presence in the cytoplasmic tail of immunoreceptor tyrosine-based activatory motifs (ITAM), as in ILT1, or inhibitory motifs (ITIM), as in IL2 to ILT10. A connection between ILTs and tolerance induction has been established by the observation that CD8+CD28- suppressor T cells upregulate ILT3 and ILT4 expression on DCs, rendering them tolerogenic. Such tolerogenic DCs have been reported to anergize alloreactive CD4+CD45RO+CD25+ T cells converting them into regulatory T cells which, in turn, continue the cascade of suprpession by toelrizing other DCs.

It has also been reported that incubation of monocyte derived human DCs, either immature or during maturation with 1,25(OH)2D3 leads to a selective upregulation of ILT3. Analysis of DC subsets revelaed a higher ILT3 expression on plasmacytoid dCs comapred to M-DCs.

PD-1 (Programmed cell death 1): In addition to B7.1, B7.2, CD40, mature DCs express recently identified B7-DC/PD-L2, B7-DC/PD-L2 which acts as ligands for PD.1, a receptor expressed on activatd T cells. This interaction has been reported to activate or suppress T cell responses.