Regulatory Dendritic Cells, T Cell Tolerance, and Dendritic Cell Therapy for Immunologic Disease

Abstract

Dendritic cells (DC) are antigen-presenting cells that can communicate with T cells both directly and indirectly, regulating our adaptive immune responses against environmental and self-antigens. Under some microenvironmental conditions DC develop into anti-inflammatory cells which can induce immunologic tolerance. A substantial body of literature has confirmed that in such settings regulatory DC (DCreg) induce T cell tolerance by suppression of effector T cells as well as by induction of regulatory T cells (Treg). Many in vitro studies have been undertaken with human DCreg which, as a surrogate marker of antigen-specific tolerogenic potential, only poorly activate allogeneic T cell responses. Fewer studies have addressed the abilities of, or mechanisms by which these human DCreg suppress autologous effector T cell responses and induce infectious tolerance-promoting Treg responses. Moreover, the agents and properties that render DC as tolerogenic are many and varied, as are the cells’ relative regulatory activities and mechanisms of action. Herein we review the most current human and, where gaps exist, murine DCreg literature that addresses the cellular and molecular biology of these cells. We also address the clinical relevance of human DCreg, highlighting the outcomes of pre-clinical mouse and non-human primate studies and early phase clinical trials that have been undertaken, as well as the impact of innate immune receptors and symbiotic microbial signaling on the immunobiology of DCreg.

Targeting DCs for Tolerance Induction: Don’t Lose Sight of the Neutrophils

“…The use of 1,25-dihydroxyvitamin D3, calcitriol, the active form of VD3, is one of the most widely established protocols for the generation of tolerogenic DCs ( 36 , 68 ). VD3 activates intracellular metabolic pathways in DCs via the PI3K/Akt/mTOR pathway that regulates glycolysis, retaining DCs in a more immature state with reduced expressions of CD80/86 and HLA-DR ( 36 , 69 , 70 ).…”

“…Other well-recognized tolerogenic adjuvants are CS, which exert immunosuppressive effects via NFκB inhibition ( 36 , 68 , 76 ). Dexamethasone (Dex) is a commonly used synthetic CS.…”

“…The tolerogenic DC features induced by Dex and VD3 largely overlap ( 36 , 48 ) and may be complementary. Therefore, Dex and VD3 are also used simultaneously to induce tolerogenic DCs ( 35 , 68 , 78 ), given that both adjuvants endow DCs with a wide range of tolerogenic properties.…”

Promoting athero-protective immunity by vaccination with low density lipoprotein-derived antigens

“…Injection of dendritic cells tolerized for LDL by pre-incubation with apoB100 and IL-10 was found to reduce atherosclerosis by 70% in ldlr − /− mice with a transgenic expression of human apoB100 [121]. Moreover, early clinical trials have indicated positive effects of tolerogenic dendritic cell therapy in rheumatoid arthritis and Crohn's disease [126].…”

New Therapeutic Approaches for Allergy: A Review of Cell Therapy and Bio- or Nano-Material-Based Strategies

“…In allergic reactions, the use of naturally-occurring or induced tolerogenic dendritic cells (tDCs) may be a prophylactic and therapeutic option to control exacerbated immune responses [17]. The techniques of isolation and reprogramming of DCs toward tolerogenic profiles are well characterized, the latter including treatment with some cytokines such as transforming growth factor (TGF)-β, interleukin (IL)-10, and/or pharmacological agents such as corticosteroids or rapamycin [18]. There are studies showing that bone marrow-derived DCs exposed in vitro to IL-10 and transferred to ovalbumin (OVA)-induced allergic mice reduced airway hyperresponsiveness, eosinophilia, and Th2 cytokine release [19].…”