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This article was submitted to Frontiers in Antigen Presenting Cell Biology, a specialty of Frontiers in Immunology.
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Peripheral immune tolerance requires a controlled balance between the maintenance of self-tolerance and the capacity to engage protective immune responses against pathogens. Dendritic cells (DCs) serve as sentinels of the immune system by sensing environmental and inflammatory signals, and play an essential role in the maintenance of immune tolerance. To achieve this, DC play a key role in dictating the outcome of immune responses by influencing the balance between inflammatory or Foxp3+ regulatory T (Treg) cell responses. At the heart of this immunological balance is a finely regulated DC and Treg cell crosstalk whereby Treg cells modulate DC phenotype and function, and DC drive the differentiation of Foxp3+ Treg cells in order to control immune responses. This review will focus on recent advances, which highlight the importance of this bidirectional DC and Treg cell crosstalk during the induction of tolerance and organ-specific autoimmunity. More specifically, we will discuss how Treg cells modulate DC function for the suppression of inflammatory responses and how DC subsets employ diverse mechanisms to drive differentiation of Treg cells. Finally, we will discuss the therapeutic potential of tolerogenic DCs for the induction of tolerance in autoimmune diseases.
Immune tolerance consists of two main processes, namely central and peripheral tolerance. Central tolerance takes place in the thymus where most of the self-reactive T cells are deleted at an immature stage of their development (
In order to ensure tolerance induction of such auto-reactive T cells in the peripheral immune system, a number of mechanisms including a network of regulatory T (Treg) cells exist to achieve this function. Treg cells constitute 1–10% of thymic and peripheral CD4+ T cells in humans and mice, and arise during a thymic selection (
Numerous studies show that different cell populations of the innate immune system such as dendritic cells (DCs), macrophages, natural killer cells, and γδ T cells can regulate tolerance induction (
Dendritic cells receive the maturation signals through the pathogen associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs) receptors that detect certain microbial and tissue damage signals
While potently capable to initiate inflammatory responses, DCs also play an important role in modulating tolerance induction. Tolerogenic DCs are characterized by high antigen uptake and processing capabilities in order to present antigen to antigen-specific T cells, but fail to deliver proper co-stimulatory signal for effector T (Teff) cells activation and proliferation (
Different DCs subsets are specialized in tolerance vs. inflammatory immune response decisions. Specific markers capable of discriminating tolerogenic from inflammatory DCs are still ill-defined. However, CD8+ DCs expressing CD95L and DEC205 often possess tolerogenic properties (
While several environmental factors and cytokines can promote the tolerogenic phenotype of DCs, there is accumulating evidence that Treg cells can also induce a tolerogenic phenotype in DCs by modulating their maturation and function. Several studies indicate that Treg cells can suppress the capacity of DCs to activate Teff cells by down-regulating CD80/CD86 expression on bone marrow-derived or splenic DCs
The production and activity of the immunomodulatory cytokine IL-10 is often associated with tolerogenic responses. IL-10 inhibits multiple aspects of DC function including MHCI/II and CD80/CD86 co-stimulatory molecules expression and a release of pro-inflammatory cytokines such as IL-1β, IL-6, TNF-α, and IL-12 (
CTLA-4 plays an important role in Treg cell-mediated suppression (
A number of other mechanisms have been proposed by which Treg cells can either abrogate the antigen presenting capacity of DCs or promote the secretion immunomodulatory cytokines. For example, Treg cells are able to induce the expression of B7-H and B7-H4, a ligands responsible for negative regulation of cell-mediated immunity in peripheral tissues (
Lymphocyte activation gene 3 is cell surface molecule expressed on Treg cells that can modulate DC phenotype and function (
It has been shown that Treg cells are more motile that naïve T cells
Recently it has been shown that neuropilin (Nrp-1) also plays a critical role in mediating Treg–DC interactions (
The results described above demonstrate the capacity of Foxp3+ Treg cells, through the expression of LAG3 and Nrp-1 molecules, to influence immature but not mature DCs. Mature DCs, in contrast to immature DCs, produce pro-inflammatory cytokines such as IL-6, TNF-α, and IL-1β which can down-regulate Foxp3 expression and abolish Foxp3+ Treg cell-mediated suppression (
In other instances, it has been demonstrated that Treg cells, through the expression of LFA-1 and CTLA-4, can suppress TNF and LPS maturated DCs by selectively down-regulating CD80, CD86, PDL1, and PDL2, but not MHCII and CD40, expression on the DC surface. Overall, these findings demonstrate that Treg cells may employ specific mechanism(s) to suppress DCs functions in different microenvironments of antigen priming.
The identification of tolerogenic DCs subsets in microenvironments such as gut, skin, and lungs suggest that local signals induce tolerogenic DCs
Recent studies show that immature DCs can uptake apoptotic and necrotic DCs without being recognized as an inflammatory event (
In the steady state, DCs are largely immature and present antigens to T cells in tolerogenic manner. Such DCs are characterized by low expression of CD80, CD86, and CD40 (
Despite the established role of immature DCs as inducers of Treg cells, recent studies have shown that mature DCs, expressing high levels of CD86, also have the potential to preferentially expand Treg cells
Dendritic cells can secrete high amounts of IL-10 upon stimulation and drive differentiation of naïve T cells into IL-10 secreting Tr1 cells (
TNF-α can also induce tolerogenic state in DCs (
TGF-β-producing DCs might preferentially drive differentiation of Treg cells rather than Teff cells. Tumor-bearing mice contains a CD11c+ DC subset characterized by low expression of CD80 and CD86 co-stimulatory molecules and are endowed with the capacity to secrete TGF-β which promotes Treg cells differentiation and proliferation
We and others have shown that a local deficiency in islets of IL-2, a critical cytokine for the homeostasis/fitness of Treg cells
It has been previously shown that CD40/CD40L interaction regulates Treg cells homeostasis (
Dendritic cells populations expressing IDO play a critical role in immune tolerance by promoting iTreg cells differentiation (
It has been shown that DCs and medullary thymic epithelial cells (mTECs) contribute to the selection of Foxp3+ Treg cells in the thymus. Epithelial cells in Hassall’s corpuscles in the thymus produce thymic stromal lymphopoietin (TSLP) which subsequently acts on thymic DCs by binding to TSLP receptor (TSLPR) and IL-7Rα complex and drives induction of CD80 and CD86 (
Dendritic cells from the lamina propria of the small intestine preferentially promote Treg cell induction relative to the DCs of lymphoid organs. This increased induction of Treg cells has been shown to be dependent on TGF-β and retinoic acid (RA), a vitamin A metabolite highly expressed in small intestine (
Wnt-β-catenin signaling in intestinal DCs regulates the balance between inflammatory and regulatory responses. Recently,
Many of the unique properties of intestinal DCs appear to be a result of environmental conditioning. Activation of NF-κB expression in intestinal epithelial cells, perhaps as a result of microflora signaling through PRRs, enhances TSLP production (
Overall, these findings illustrate that the intestinal immune system (i.e., GALT) is a preferential site for the induction of Treg cells, and provides a mechanism by which the thymus-derived Treg cell pool could be complemented by
Like the intestine, the skin and lungs are also constantly exposed to various microbes and environmental antigens such as allergens. The interaction between vitamin D and RANK–RANKL signaling pathway in the skin plays a role in DC-mediated iTreg cells induction (
The possibility to generate or expand tolerogenic DCs
Our understanding of the functional and phenotypic plasticity of DCs, as well the capacity to modulate DCs development and maturation
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.