RelB+ Steady-State Migratory Dendritic Cells Control the Peripheral Pool of the Natural Foxp3+ Regulatory T Cells.

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.

Neuromelanin is an immune stimulator for dendritic cells in vitro.

BACKGROUND: Parkinson'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. RESULTS: Murine 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 (CD86(high)/MHCII(high)). 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. CONCLUSIONS: NM 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.

Steady state migratory RelB+ langerin+ dermal dendritic cells mediate peripheral induction of antigen-specific CD4+ CD25+ Foxp3+ regulatory T cells.

Tolerance to self-antigens expressed in peripheral organs is maintained by CD4(+) CD25(+) Foxp3(+) 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(+) phenotype, used endogenous TGF-ß for conversion and showed nuclear RelB translocation. Deficiency of the alternative NF-κB 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(+) OVA-specific TCR-transgenic OT-II T cells. The langerin(+) dermal DC subset, but not epidermal Langerhans cells, mediated conversion of naive OT-II×RAG-1(-/-) T cells into proliferating CD4(+) CD25(+) Foxp3(+) Tregs. Thus, our data suggest that steady-state migratory RelB(+) TGF-ß(+) langerin(+) dermal DCs mediate peripheral Treg conversion in response to epidermal antigen in skin-draining lymph nodes.

Role of dendritic cell maturity/costimulation for generation, homeostasis, and suppressive activity of regulatory T cells.

Tolerogenicity of dendritic cells (DCs) has initially been attributed exclusively to immature/resting stages, while mature/activated DCs were considered strictly immunogenic. Later, all different subsets among the myeloid/conventional DCs and plasmacytoid DCs have been shown to bear tolerogenic potential, so that tolerogenicity could not be attributed to a specific subset. Immunosuppressive treatments of immature DC subsets could prevent re-programming into mature DCs or upregulated inhibitory surface markers or cytokines. Furthermore, the different T cell tolerance mechanisms anergy, deletion, immune deviation, and suppression require different quantities and qualities of costimulation by DCs. Since expansion of regulatory T cells (Tregs) has been shown to be promoted best by fully mature DCs the role of CD80/B7-1 and CD86/B7-2 as major costimulatory molecules for Treg biology is under debate. In this review, we discuss the role of these and other costimulatory molecules on myeloid DCs and their ligands CD28 and CD152/CTLA-4 on Tregs for peripheral conversion from naive CD4⁺ T cells into the major subsets of Foxp3⁺ Tregs and Foxp3⁻ IL-10⁺ regulatory type-1 T cells (Tr1) or Tr1-like cells and their role for peripheral maintenance in the steady state and after activation.

Revisiting the tolerogenicity of epidermal Langerhans cells.

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-beta1, 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. Transfer of antigens from LC to other DC subsets as well as transport of HIV are discussed as part of the complex interactions between LC and other cells or as mechanisms of immune evasion. Finally, the first clinical trials on allergy therapies targeting skin DC in the steady state are mentioned as they may open the door to curative tolerogenic therapies.