Tolerance to self-antigens expressed in peripheral organs is maintained by CD4 1 CD25 1 Foxp31 Treg cells, which are generated as a result of thymic selection or peripheral induction.Here, we demonstrate that steady-state migratory DCs from the skin mediated Treg conversion in draining lymph nodes of mice. These DCs displayed a partially mature MHC II int CD86 int CD40 hi CCR7 1 phenotype, used endogenous TGF-b for conversion and showed nuclear RelB translocation. Deficiency of the alternative NF-jB signaling pathway (RelB/p52) reduced steady-state migration of DCs. These DCs transported and directly presented soluble OVA provided by s.c. implanted osmotic minipumps, as well as cell-associated epidermal OVA in transgenic K5-mOVA mice to CD4 1 OVA-specific TCR-transgenic OT-II T cells. 1420antigens drained from peripheral tissues can be taken up from the fluid phase for presentation to T cells under steady-state conditions [4]. Recently, it has been reported that continuous peripheral antigen delivery can induce Treg conversion in draining lymph nodes. This suggests that the reticular conduit system delivers exogenous peptides under non-immunogenic conditions, which can be mimicked by implanted osmotic pumps, to lymph node-resident immature DCs, which then present these peptides to induce Tregs in vivo [5].Such mechanisms of antigen delivery may explain the induction of CD41 T-cell anergy as shown for antigen presentation by immature DCs expressing only low levels of MHC II and costimulatory molecules [6]. However, it does not explain how immature DCs may induce CD4 1 Treg since B7-1/B7-2 À/À and CD28 À/À mice lack CD4 1 CD25 1 Tregs despite the presence of immature DCs [7]. Splenic DCs converted Treg better than B cells, and CD80/86-deficiency of the DCs further increases the conversion. These conversion experiments were either in vitro studies or under a pathological situation (tumor) but not steady state [8]. Later, the splenic CD8a 1 DC subset was identified as mediating conversion after injection of a DEC205-targeting antibody [9]. The physiological relevance of splenic DCs or DEC205 for Treg conversion with self-antigens remains open. A CD103 1 DC population has been isolated from mesenteric lymph nodes that mediated TGF-b-dependent Treg conversion in culture, but the maturation stage of the DC has not been analyzed [10]. In contrast, a CD103 À DC subset within skin-draining lymph nodes was responsible for Treg conversion in vitro [11]. This indicates that CD103 expression by DCs is not correlated with their capacity to convert Tregs and a specific phenotype for DCs inducing Tregs under steady-state conditions and in vivo remains to be identified [12]. Fluid phase soluble antigen transport also does not explain how lymph node T cells can be tolerized against cell-associated antigens. Therefore, the presentation of self-antigens by migratory DCs has been suggested as a mechanism of peripheral tolerance since these cells can be observed in draining lymph nodes of various organs [13,14]. The mature CCR7-expre...

Langerhans cells (LC) are unique members of the dendritic cell (DC) family residing in the epidermis of skin and mucosa. Specific autocrine and environmental factors shape the biology of LC, such as TGF-b1, IL-10, vitamin D 3 , UV light or neuropeptides, which are required for LC development but also influence their capacity to induce immunity or tolerance. Both, immunogenic and tolerogenic functions require antigen transport from the skin to the draining lymph nodes, but the LC maturation grade directs the differential outcome. In this review, we recapitulate early indications for LC tolerogenicity and oppose them to more recent findings with gene-targeted mice, which dramatically challenged some of the early results. The newly discovered Langerin + dermal DC subset (DDC) seems to be responsible also for many tolerogenic effects that were initially attributed to steady state migratory LC. Keywords: dendritic cells; Langerhans cells; tolerance; steady state EARLY REPORTS ABOUT LC TOLEROGENICITY Epidermal LC were originally described as nerve cells. 1 Only much later their hematopoietic origin was recognized 2 and due to their strong potential to mature into T-cell stimulatory cells they were attributed to the DC family. 3 Very early reports showed that LC ingested epidermal self-antigens such as melanosomes 4 or apoptotic cells, 5 degraded proteins 6 and transported them to the draining lymph nodes under steady state conditions. 7-9 The rate of transported selfantigen seemed very constant and was not altered under inflammatory conditions. 10 Self-antigen transport by antigen-presenting LC to the lymph nodes should have functional consequences for T cells. Conventional and cross-presentation of self-antigens by tolerogenic DC has been reported in various tissues. 11 NEW ASPECTS ON LC TOLEROGENICITYThe identification of a new subset of Langerin + dermal DC subset (DDC) and their functional analyses changed the view on several LC functions. 12 Differences between these skin DC subsets were addressed by using novel genetic mouse models. 13 Nevertheless, the precise role of LC in tolerance induction is still not fully understood.Unlike splenic DC, one report indicated that LC isolated from epidermal sheets negatively regulated naive CD4 T-cell activation in vitro. 14 Although this is not supported by other reports, [15][16][17] there are examples where migrated LC only upregulated CD40 after contact sensitizer activation, thus largely lacking T-cell costimulation via CD28, whereas migrated DDC upregulated both CD80 and CD86. 18 Furthermore, LC were not shown to be required for efficient skin graft rejection. 19 All these results would indicate tolerogenic functions of LC.The use of Langerin-DTR mice revealed that LC are not required for UV-B light induced immunosuppression. 20 These evidences would argue against a role for LC in tolerance induction. Further pros and cons on LC tolerogenicity have been discussed before [21][22][23] and additional examples are given below. TOLEROGENIC FACTORS IN THE LC ENVIRONMENTThere...

BackgroundParkinson's disease (PD) is characterized at the cellular level by a destruction of neuromelanin (NM)-containing dopaminergic cells and a profound reduction in striatal dopamine. It has been shown recently that anti-melanin antibodies are increased in sera of Parkinson patients, suggesting that NM may act as an autoantigen. In this study we tested whether NM is being recognized by dendritic cells (DCs), the major cell type for inducing T- and B-cell responses in vivo. This recognition of NM by DCs is a prerequisite to trigger an adaptive autoimmune response directed against NM-associated structures.ResultsMurine DCs were treated with NM of substantia nigra (SN) from human subjects or with synthetic dopamine melanin (DAM). DCs effectively phagocytized NM and subsequently developed a mature phenotype (CD86high/MHCIIhigh). NM-activated DCs secreted the proinflammatory cytokines IL-6 and TNF-α. In addition, they potently triggered T cell proliferation in a mixed lymphocyte reaction, showing that DC activation was functional to induce a primary T cell response. In contrast, DAM, which lacks the protein and lipid components of NM but mimics the dopamine-melanin backbone of NM, had only very little effect on DC phenotype and function.ConclusionsNM is recognized by DCs in vitro and triggers their maturation. If operative in vivo, this would allow the DC-mediated transport and presentation of SN antigens to the adaptive immune system, leading to autoimmmunity in susceptible individuals. Our data provide a rationale for an autoimmune-based pathomechanism of PD with NM as the initial trigger.

Thymus-derived natural Foxp3+ CD4+ regulatory T cells (nTregs) play a key role in maintaining immune tolerance and preventing autoimmune disease. Several studies indicate that dendritic cells (DCs) are critically involved in the maintenance and proliferation of nTregs. However, the mechanisms how DCs manage to keep the peripheral pool at constant levels remain poorly understood. Here, we describe that the NF-κB/Rel family transcription factor RelB controls the frequencies of steady-state migratory DCs (ssmDCs) in peripheral lymph nodes and their numbers control peripheral nTreg homeostasis. DC-specific RelB depletion was investigated in CD11c-Cre × RelBfl/fl mice (RelBDCko), which showed normal frequencies of resident DCs in lymph nodes and spleen while the subsets of CD103− Langerin− dermal DCs (dDCs) and Langerhans cells but not CD103+ Langerin+ dDC of the ssmDCs in skin-draining lymph nodes were increased. Enhanced frequencies and proliferation rates were also observed for nTregs and a small population of CD4+ CD44high CD25low memory-like T cells (Tml). Interestingly, only the Tml but not DCs showed an increase in IL-2-producing capacity in lymph nodes of RelBDCko mice. Blocking of IL-2 in vivo reduced the frequency of nTregs but increased the Tml frequencies, followed by a recovery of nTregs. Taken together, by employing RelBDCko mice with increased frequencies of ssmDCs our data indicate a critical role for specific ssmDC subsets for the peripheral nTreg and IL-2+ Tml frequencies during homeostasis.