Balancing between immunity and tolerance: an interplay between dendritic cells, regulatory T cells, and effector T cells

Abstract

Dendritic cells (DC), professional antigen-presenting cells of the immune system, exert important functions both in induction of T cell immunity, as well as tolerance. It is well established that the main function of immature DC (iDC) in their in vivo steady-state condition is to maintain peripheral tolerance to self-antigens and that these iDC mature upon encounter of so-called danger signals and subsequently promote T cell immunity. Previously, it was believed that T cell unresponsiveness induced after stimulation with iDC is caused by the absence of inflammatory signals in steady-state in vivo conditions and by the low expression levels of costimulatory molecules on iDC. However, a growing body of evidence now indicates that iDC can also actively maintain peripheral T cell tolerance by the induction and/or stimulation of regulatory T cell populations. Moreover, several reports indicate that traditional DC maturation can no longer be used to distinguish tolerogenic and immunogenic properties of DC. This review will focus on the complementary role of dendritic cells in inducing both tolerance and immunity, and we will discuss the clinical implications for dendritic cell-based therapies.

Lipopolysaccharide‐primed heterotolerant dendritic cells suppress experimental autoimmune uveoretinitis by multiple mechanisms

“…DC play an important role in the priming of the adaptive immune response due to their ability to directly stimulate naive T cells. However, one of their main functions appears to be a homeostatic one of maintaining tolerance to self‐antigens 8, 9, 10, 11, 12. Recently autologous tolerogenic DC (tolDC) modified in vitro with a nuclear factor‐ κ B (NF‐ κ B) inhibitor and loaded with citrullinated peptide antigens have been successfully used to treat patients with rheumatoid arthritis in a Phase 1 clinical trial 13.…”

Abatacept Inhibition of T Cell Priming in Mice by Induction of a Unique Transcriptional Profile That Reduces Their Ability to Activate Antigen‐Presenting Cells

“…T cells require both T cell receptor (TCR) and costimulatory signals for activation and differentiation (2). Antigen presentation in the absence of costimulation can result in impaired clonal expansion, anergy, or the generation of Treg cells (3,4).…”

MHC Class II Antigen Presentation by Dendritic Cells Regulated through Endosomal Sorting

“…Characteristic features of DC differentiation or "maturation" include a transient increase in phagocytosis and macropinocytosis for efficient antigen uptake, increased surface expression of costimulatory molecules (e.g., CD86, CD80, CD40), and enhanced potential to migrate from peripheral tissues to the local lymphoid tissues for interaction with T cells (West et al 2004; Reis e Sousa 2006). Several other stimuli, for example, TNF-a, can drive alternative DC maturation programs that result in tolerogenic rather than immunogenic DCs (Menges et al 2002;Tan and O'Neill 2005;Cools et al 2007;Maldonado and von Andrian 2010).…”