We recognize well the abilities of dendritic cells to activate effector T cell (Teff cell) responses to an array of antigens and think of these cells in this context as pre-eminent antigen-presenting cells, but dendritic cells are also critical to the induction of immunologic tolerance. Herein, we review our knowledge on the different kinds of tolerogenic or regulatory dendritic cells that are present or can be induced in experimental settings and humans, how they operate, and the diseases in which they are effective, from allergic to autoimmune diseases and transplant tolerance. The primary conclusions that arise from these cumulative studies clearly indicate that the agent(s) used to induce the tolerogenic phenotype and the status of the dendritic cell at the time of induction influence not only the phenotype of the dendritic cell, but also that of the regulatory T cell responses that they in turn mobilize. For example, while many, if not most, types of induced regulatory dendritic cells lead CD4+ naïve or Teff cells to adopt a CD25+Foxp3+ Treg phenotype, exposure of Langerhans cells or dermal dendritic cells to vitamin D leads in one case to the downstream induction of CD25+Foxp3+ regulatory T cell responses, while in the other to Foxp3− type 1 regulatory T cells (Tr1) responses. Similarly, exposure of human immature versus semi-mature dendritic cells to IL-10 leads to distinct regulatory T cell outcomes. Thus, it should be possible to shape our dendritic cell immunotherapy approaches for selective induction of different types of T cell tolerance or to simultaneously induce multiple types of regulatory T cell responses. This may prove to be an important option as we target diseases in different anatomic compartments or with divergent pathologies in the clinic. Finally, we provide an overview of the use and potential use of these cells clinically, highlighting their potential as tools in an array of settings.

Background. Semi-mature IL-10-induced DC (DC10) induce human or mouse effector Th2 cells (Teff) to differentiate into Foxp3+ Treg and thereby induce asthma tolerance. Retinoic acid (RA) and TGFβ-induced gut DC similarly induce tolerance to gut contents via Foxp3+ Treg, while immature hDC-10 induce IL-10-dependent Foxp3- Tr1 cells. Methods. We assessed the abilities of mature RA-induced DC to reverse anaphylaxis sensitivity, characterizing LPS-matured DC-RA and their tolerogenic activities in mouse models of OVA and peanut systemic anaphylaxis. Results. Mature DC-RA strongly expressed CD103 (αE integrin), MHCII, co-stimulatory markers, PDL1 & -L2, ICOSL, TGFβ, IL-27 and the RA-metabolizing enzyme Aldh1A2. They induced Th2 cells to convert into CD25+LAG3+CD49b-IL-10-Foxp3- Treg in an IL-10-independent, IL-27-dependent fashion, although IL-27 was dispensable for Th2 suppression by DC-RA. Wild-type, but not IL-27-/- DC-RA therapy reversed systemic anaphylaxis, including clinical scores, diarrhea, mast cell activation and Th2 responses, and lowered serum allergen-specific IgE and IgG1 levels. Conclusions. Allergen-presenting DC-RA induce food allergen tolerance by activating CD25+Foxp3-, non-Tr1 responses in an IL-27-dependent fashion. This data indicates that, like DC10, DC-RA can also be used for allergic disease immunotherapy, but that these two populations of DCreg induce distinct Treg responses, and this potentially provides us with important options DCreg immunotherapy