How Tolerogenic Dendritic Cells Induce Regulatory T Cells

Abstract

Since their discovery by Steinman and Cohn in 1973, dendritic cells (DCs) have become increasingly recognized for their crucial role as regulators of innate and adaptive immunity. DCs are exquisitely adept at acquiring, processing and presenting antigens to T cells. They also adjust the context (and hence the outcome) of antigen presentation in response to a plethora of environmental inputs that signal the occurence of pathogens or tissue damage. Such signals generally boost DC maturation, which promotes their migration from peripheral tissues into and within secondary lymphoid organs and their capacity to induce and regulate effector T cell responses. Conversely, more recent observations indicate that DCs are also crucial to ensure immunological peace. Indeed, DCs constantly present innocuous self and non-self antigens in a fashion that promotes tolerance, at least in part, through the control of regulatory T cells (Tregs). Tregs are specialized T cells that exert their immuno-suppressive function through a variety of mechanisms affecting both DCs and effector cells. Here, we review recent advances in our understanding of the relationship between tolerogenic DCs and Tregs.

Tolerogenic nanoparticles to induce immunologic tolerance: Prevention and reversal of FVIII inhibitor formation

“…The tolerogenic nanoparticle (SVP) are made with a polymer, PLGA, that is biocompatible, biodegradable and used in multiple products licensed for clinical use by regulatory agencies [28]. We have combined it with an immunomodulatory agent, rapamycin, which has been validated in humans and is capable of facilitating tolerance [10,20,21,29,30]. The delivery of rapamycin by nanoparticles allows for efficient transport to lymphoid organs and capture by phagocytic antigen presenting cells (APCs) [20], and thus reduce non-specific toxicity through chronic systemic administration.…”

“…Strategies to induce tolerance include conjugating antigen to splenocytes [8], immature dendritic cells (DC) [9,10], or synthetic microparticles [11,12], oral tolerance [13], gene therapy [14] or co-treatment with immunosuppressive drugs, such as methotrexate [15]. Recently, it has been reported that systemic co-administration of rapamycin, a immunosuppressant drug commonly used to prevent transplant rejection, prevented immune response and induced tolerance to FIX and FVIII in mouse models of hemophilia A and B, respectively [29,30].…”

“…Based on the advantage of using a therapeutic nanoparticle delivery system [16][17][18][19], as well as the evidence that rapamycin treatment promotes tolerance induction both in vitro and in vivo [10,21,29,30], we developed tolerogenic synthetic vaccine particles (SVP) by incorporating rapamycin in self-assembling, biodegradable nanoparticles comprised of poly(lactic-co-glycolic acid) (PLGA), a polymer found in multiple medical products [20]. The use of these tolerogenic nanoparticles incorporating rapamycin could eliminate the need for chronic use of immunosuppressive systemic drugs.…”

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).…”

Helicobacter pylori γ-glutamyl transpeptidase and vacuolating cytotoxin promote gastric persistence and immune tolerance

“…The depletion of Tregs in a genetic model resulted in spontaneous clearance of the infection (9) and greatly improved the efficacy of an H. pylori vaccine (10). H. pylori-induced Tregs differentiate in the periphery as a result of their priming by tolerogenic DCs (13), which convert naive T cells into FoxP3 + Tregs through antigen presentation in the absence of costimulatory signals or cytokines (13,14). We have shown recently that H. pylori exposure reprograms DCs toward a tolerance-promoting phenotype in vitro and in vivo; H. pyloriexperienced DCs fail to induce T-cell effector functions, but rather acquire the ability to induce FoxP3 and CD25 expression in cocultured naive T cells (12).…”