Regulatory dendritic cells for immunotherapy in immunologic diseases

Abstract

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.

Keywords: IL-10; TGFβ; dendritic cell; immunoregulation; regulatory T cell; retinoic acid; tolerance; vitamin D.

Figure 1

Induction of immunologic tolerance by regulatory dendritic cells. Immature or semi-mature dendritic cells that are incubated with, or differentiated in the presence of, tolerogenic factors (e.g., IL-10, vitamin D3, corticosteroids, or retinoic acid) (1) adopt a regulatory phenotype. When these converted regulatory dendritic cells are pulsed with antigen and exposed to cognate naïve or effector T (Teff) cells (2), they present their processed antigen peptides in the context of MHCII, and also lower levels of co-stimulation (e.g., CD40, CD86) to the T cells, but at the same time many types of tolerogenic cells also provide inhibitory receptor (e.g., ILT2, ILT4) signaling to the T cell. Counter-signaling from the engaged T cell activates dendritic cell production of polarizing mediators (e.g., IL-10, TGFβ), which together instruct the T cell to adopt a regulatory phenotype. The nature of the instructional signals from the dendritic cell to the T cell determine whether it adopts an IL-10-secreting CD25⁺Foxp3⁺ Treg phenotype or an IL-10/TGFβ-secreting Foxp3⁻ Tr1 phenotype (3). These regulatory T cells are able to suppress the responses of cognate or by-stander naïve or effector T cells in their microenvironment (4) and also to convert endogenous tissue dendritic cells to adopt a regulatory phenotype through induction of infectious tolerance (5), and thereby reinforce the tolerance phenotype.