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. 2012 Jul 3:3:183.
doi: 10.3389/fimmu.2012.00183. eCollection 2012.

Layers of dendritic cell-mediated T cell tolerance, their regulation and the prevention of autoimmunity

Christian T Mayer  1 , Luciana Berod, Tim Sparwasser
Affiliations

Layers of dendritic cell-mediated T cell tolerance, their regulation and the prevention of autoimmunity

Christian T Mayer et al. Front Immunol. .

Abstract

The last decades of Nobel prize-honored research have unequivocally proven a key role of dendritic cells (DCs) at controlling both T cell immunity and tolerance. A tight balance between these opposing DC functions ensures immune homeostasis and host integrity. Its perturbation could explain pathological conditions such as the attack of self tissues, chronic infections, and tumor immune evasion. While recent insights into the complex DC network help to understand the contribution of individual DC subsets to immunity, the tolerogenic functions of DCs only begin to emerge. As these consist of many different layers, the definition of a "tolerogenic DC" is subjected to variation. Moreover, the implication of DCs and DC subsets in the suppression of autoimmunity are incompletely resolved. In this review, we point out conceptual controversies and dissect the various layers of DC-mediated T cell tolerance. These layers include central tolerance, Foxp3(+) regulatory T cells (Tregs), anergy/deletion and negative feedback regulation. The mode and kinetics of antigen presentation is highlighted as an additional factor shaping tolerance. Special emphasis is given to the interaction between layers of tolerance as well as their differential regulation during inflammation. Furthermore, potential technical caveats of DC depletion models are considered. Finally, we summarize our current understanding of DC-mediated tolerance and its role for the suppression of autoimmunity. Understanding the mechanisms of DC-mediated tolerance and their complex interplay is fundamental for the development of selective therapeutic strategies, e.g., for the modulation of autoimmune responses or for the immunotherapy of cancer.

Keywords: CD103; DC; Foxp3; Treg; autoimmunity; infection; tolerance.

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Figures

Figure 1
Figure 1
Classical models of DC-mediated tolerance. It is a long standing controversy how DCs mediate immunological tolerance. (A) One classical view is that the maturation status of DCs acts as a switch, determining the decision for either tolerance in the steady state (immature/semimature DCs) or for immunity upon inflammation (mature DCs). (B) The subsequent discovery of immunosuppressive regulatory T cells that can be activated by both immature and mature DCs, raised the possibility for functional dichotomy. This means that a DC is capable of potentially executing both tolerogenic and immunogenic immune responses as parallel events. (C) Certain DC subsets were proposed to be inherently more potent in tolerance induction compared to other DC subsets. In this model, a division of labor between DC subsets regulates tolerance versus immunity.
Figure 2
Figure 2
Layers of DC-mediated tolerance. DCs promote tolerance via multiple layers, thereby rendering the term “tolerogenic DC” highly indefinite. (A) DCs are implicated in the negative selection of self-reactive T cells and thus in central tolerance, although this is still a subject of intense research. (B) DCs are critically involved in the de novo generation, homeostasis and activation of Foxp3+ Tregs which play a non-redundant role in the suppression of lethal autoimmunity. Foxp3+ Treg activation by DC-associated MHC-class-II: peptide complexes and CD80/CD86 is crucial to activate the immunosuppressive properties of Foxp3+ Tregs and to induce their expansion. Additionally, IL-2 and TGF-β, which can be produced by DCs, are critically involved in the maintenance of Treg function and proliferation. DC-derived TGF-β can also act on Foxp3− T cells to convert them into Foxp3+ Tregs. This process is enhanced by retinoic acid (RA) which is generated in DCs from retinaldehyde by the enzyme Raldh2. PD-1 ligands (PD-L1 and PD-L2) were also implied in Foxp3+ Treg induction. (C) Recessive peripheral tolerance is established in a T cell-intrinsic manner following instructive encounters with DCs. Antigenic activation of Foxp3− T cells can result in their functional inactivation (clonal anergy). This partly depends on the triggering of PD-1 on T cells via its ligands PD-L1 and PD-L2. Similarly, signaling via CTLA-4 can induce clonal anergy (not depicted). Another outcome of recessive tolerance can be clonal T cell deletion which depends on interactions via TNF/TNFR2, FasL/Fas or induction of the pro-apoptotic factor Bim. (D) Multiple mechanisms can result in the feedback inhibition of DCs. Foxp3+ Tregs bind the co-stimulatory molecules CD80/CD86 on DCs via CTLA-4. This interaction leads to the production of indolamine-2,3-dioxygenase (IDO) and in the suppression of DC maturation (not depicted). IDO causes the apoptosis of conventional T cells and activates Foxp3+ Tregs. TGF-β produced and activated by DCs can directly inhibit DC functions. Additionally, signaling via TLRs (e.g., TLR2), DC-SIGN and the Wnt/β-catenin pathway can result in the production of IL-10 by DCs. IL-10 potently inhibits DC maturation/function and induces IL-10-producing TR1 cells, thereby creating a regulatory feedback loop.
Figure 3
Figure 3
DCs in the suppression of autoimmunity. The role of DCs in the suppression of autoimmunity is complex and a matter of discussion. (A) In the steady state, DCs are believed to contribute to the negative selection of autoreactive T cells. Few autoreactive T cell clones that escape negative selection can be efficiently controlled by Foxp3+ Tregs in the periphery, a process that critically depends on the continuous activation and homeostasis of Tregs by DCs. Equilibrium between the production of the myeloid growth factor FLT3L and its consumption maintains a constant number of DCs and other myeloid cells. (B) DC-deficient (ΔDC) mice may exhibit defective negative selection, resulting in the increased seeding of the periphery with self-reactive T cells. Additionally, the absence of peripheral DCs impairs Foxp3+ Treg homeostasis and activation, resulting in a substantial reduction of Treg numbers and probably also functionality. The massive accumulation of FLT3L due to the absence of DCs as key consumers of this growth factor leads to a myeloproliferative syndrome. Signs of increased autoreactivity are detectable in ΔDC mice, yet the absence of DCs most likely prevents the activation of self-reactive T cells and thus the full precipitation of systemic autoimmunity. (C) The absence of functional Foxp3+ Tregs (ΔTregs; e.g., in scurfy mice) is compatible with a normal negative selection, yet provokes severe systemic autoimmunity due to the defective negative regulation of DCs and autoreactive T cells. An increased level of FLT3L in the absence of Foxp3+ Tregs expands the numbers of DCs and other myeloid cells.
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References

    1. Adler A. J., Marsh D. W., Yochum G. S., Guzzo J. L., Nigam A., Nelson W. G., Pardoll D. M. (1998). CD4+ T cell tolerance to parenchymal self-antigens requires presentation by bone marrow-derived antigen-presenting cells. J. Exp. Med. 187, 1555–1564 10.1084/jem.187.10.1555 - DOI - PMC - PubMed
    1. Akimova T., Beier U. H., Wang L., Levine M. H., Hancock W. W. (2011). Helios expression is a marker of T cell activation and proliferation. PLoS ONE 6:e24226 10.1371/journal.pone.0024226 - DOI - PMC - PubMed
    1. Anderson M. S., Venanzi E. S., Klein L., Chen Z., Berzins S. P., Turley S. J., Von Boehmer H., Bronson R., Dierich A., Benoist C., Mathis D. (2002). Projection of an immunological self shadow within the thymus by the aire protein. Science 298, 1395–1401 10.1126/science.1075958 - DOI - PubMed
    1. Annacker O., Coombes J. L., Malmstrom V., Uhlig H. H., Bourne T., Johansson-Lindbom B., Agace W. W., Parker C. M., Powrie F. (2005). Essential role for CD103 in the T cell-mediated regulation of experimental colitis. J. Exp. Med. 202, 1051–1061 10.1084/jem.20040662 - DOI - PMC - PubMed
    1. Anz D., Koelzer V. H., Moder S., Thaler R., Schwerd T., Lahl K., Sparwasser T., Besch R., Poeck H., Hornung V., Hartmann G., Rothenfusser S., Bourquin C., Endres S. (2010). Immunostimulatory RNA blocks suppression by regulatory T cells. J. Immunol. 184, 939–946 10.4049/jimmunol.0901245 - DOI - PubMed