Tolerogenic Dendritic Cells in Autoimmunity and Inflammatory Diseases

Dendritic cells (DCs) play various roles as antigen-presenting cells and participate in central and peripheral tolerance. Recent single-cell studies are redefining and expanding their classification and roles. Inflammatory dendritic cells (infDCs), derived from monocytes, play a relevant role in the course of autoimmune diseases. In vitro monocyte-derived DCs can be used in studies analyzing tolerance-inducing agents and potential therapeutics. Transcription factor-mediated and epigenetic mechanisms involved in the tolerogenic differentiation of DCs are being elucidated. DNA methylation both in vivo and in vitro has arisen as a relevant molecular mechanism in tolerogenic DC (tolDC) differentiation. TolDCs can promote tolerance towards different immune cell types involved in autoimmunity via contact-dependent interactions and by secreting pleiotropic cytokines and metabolites. Therapies centered on the administration of tolDCs are yielding promising results as alternatives to immunomodulators for certain chronic inflammatory diseases and organ transplantation, given their ability to specifically suppress autoimmune responses without inducing general immunosuppression. Dendritic cells (DCs), the most efficient antigen-presenting cells, are necessary for the effective activation of naïve T cells. DCs can also acquire tolerogenic functions in vivo and in vitro in response to various stimuli, including interleukin (IL)-10, transforming growth factor (TGF)-β, vitamin D3, corticosteroids, and rapamycin. In this review, we provide a wide perspective on the regulatory mechanisms, including crosstalk with other cell types, downstream signaling pathways, transcription factors, and epigenetics, underlying the acquisition of tolerogenesis by DCs, with a special focus on human studies. Finally, we present clinical assays targeting, or based on, tolerogenic DCs in inflammatory diseases. Our discussion provides a useful resource for better understanding the biology of tolerogenic DCs and their manipulation to improve the immunological fitness of patients with certain inflammatory conditions. Dendritic cells (DCs), the most efficient antigen-presenting cells, are necessary for the effective activation of naïve T cells. DCs can also acquire tolerogenic functions in vivo and in vitro in response to various stimuli, including interleukin (IL)-10, transforming growth factor (TGF)-β, vitamin D3, corticosteroids, and rapamycin. In this review, we provide a wide perspective on the regulatory mechanisms, including crosstalk with other cell types, downstream signaling pathways, transcription factors, and epigenetics, underlying the acquisition of tolerogenesis by DCs, with a special focus on human studies. Finally, we present clinical assays targeting, or based on, tolerogenic DCs in inflammatory diseases. Our discussion provides a useful resource for better understanding the biology of tolerogenic DCs and their manipulation to improve the immunological fitness of patients with certain inflammatory conditions. subset with regulatory functions both in mice and humans. process in which immature lymphocytes expressing high-affinity receptors for self-antigens are eliminated before finishing their differentiation. hyporesponsive state to foreign substances. event of depletion of specific lymphocyte clones via induction of apoptosis. presentation of exogenous antigens on MHC class I molecules to CD8+ T cells. endogenous molecules that can be recognized by PRRs, producing inflammatory responses. member of the zinc finger family of TFs characteristic of DCs. pathological condition following an allogeneic transplant characterized by a response of the donor immune cells to the host tissues. subset of T cells characterized by a semi-invariant T cell receptor restricted to CD1d, a class I-related molecule presenting lipid antigens. stromal cell population of the thymus medulla involved in central tolerance. small molecules from infectious organisms, common in groups of pathogens; can be recognized by PRRs, producing an inflammatory response. proteins expressed by innate immune cells that recognize PAMPs and DAMPs. mechanism of peripheral tolerance through cross-presentation of antigens by homeostatic DCs to CD8+ T cells. to avoid autoimmune responses, process of eliminating self-reactive T and B cells having escaped central tolerance. surface protein expressed on T cells, binding of which with PD-L1 can promote clonal anergy and Treg differentiation. small population of B cells participating in the suppression of immune responses. population of T cells comprehending different subsets with key roles in maintaining peripheral tolerance and immune homeostasis. in DCs, intermediate state of maturation, with low expression of co-stimulatory proteins and, generally, a tolerogenic phenotype. genomic region comprising multiple enhancers and bound by different TFs. DCs with a stable, semi-mature phenotype, that can abrogate immune responses, limiting T cell immunogenesis. family of transmembrane PRRs.