Promoting tolerance to proteolipid protein-induced experimental autoimmune encephalomyelitis through targeting dendritic cells

Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 10/2010; 107(40):17280-5. DOI: 10.1073/pnas.1010263107
Source: PubMed


In T cell-mediated autoimmune diseases, self-reactive T cells with known antigen specificity appear to be particularly promising targets for antigen-specific induction of tolerance without compromising desired protective host immune responses. Several lines of evidence suggest that delivery of antigens to antigen-presenting dendritic cells (DCs) in the steady state (i.e., to immature DCs) may represent a suitable approach to induce antigen-specific T-cell tolerance peripherally. Here, we report that anti-DEC205-mediated delivery of the self-peptide proteolipid protein (PLP)139-151 to DCs ameliorated clinical symptoms in the PLP-induced SJL model of experimental autoimmune encephalomyelitis. Splenocytes from treated mice were anergized to PLP139-151, and IL-17 secretion was markedly reduced. Moreover, we show directly, using transgenic CD4(+) Vβ6(+) TCR T cells specific for PLP139-151, that, under the conditions of the present experiments, these cells also became anergic. In addition, evidence for a CD4(+) T cell-mediated suppressor mechanism was obtained.

Download full-text


Available from: Joel N H Stern,
  • Source
    • "Regarding the suppressive function of Foxp3+ T-regs induced by antigen targeting to DCs in vivo, accumulating evidence has shown that antigen delivery to the DC subset suppresses experimental autoimmune encephalomyelitis (EAE) (Hawiger et al., 2004; Stern et al., 2010; Loschko et al., 2011; Idoyaga et al., 2013). Antigen delivery to not only DEC205+CD8+ DCs but also Langerin+DCs and pDCs led to induction of Foxp3+ T regs and suppression of EAE (Loschko et al., 2011; Idoyaga et al., 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Dendritic cells (DCs) are specialized antigen-presenting cells that regulate both immunity and tolerance. DCs in the periphery play a key role in expanding naturally occurring Foxp3(+) CD25(+) CD4(+) regulatory T cells (Natural T-regs) and inducing Foxp3 expression (Induced T-regs) in Foxp3(-) CD4(+) T cells. DCs are phenotypically and functionally heterogeneous, and further classified into several subsets depending on distinct marker expression and their location. Recent findings indicate the presence of specialized DC subsets that act to expand Natural T-regs or induce Foxp3(+) T-regs from Foxp3(-) CD4(+) T cells. For example, two major subsets of DCs in lymphoid organs act differentially in inducing Foxp3(+) T-regs from Foxp3(-) cells or expanding Natural T-regs with model-antigen delivery by anti-DC subset monoclonal antibodies in vivo. Furthermore, DCs expressing CD103 in the intestine induce Foxp3(+) T-regs from Foxp3(-) CD4(+) T cells with endogenous TGF-β and retinoic acid. In addition, antigen-presenting DCs have a capacity to generate Foxp3(+) T-regs in the oral cavity where many antigens and commensals exist, similar to intestine and skin. In skin and skin-draining lymph nodes, at least six DC subsets have been identified, suggesting a complex DC-T-reg network. Here, we will review the specific activity of DCs in expanding Natural T-regs and inducing Foxp3(+) T-regs from Foxp3(-) precursors, and further discuss the critical function of DCs in maintaining tolerance at various locations including skin and oral cavity.
    Frontiers in Immunology 06/2013; 4:151. DOI:10.3389/fimmu.2013.00151
  • Source
    • "In peripheral lymphoid tissues, naïve CD4+Foxp3? T cells can acquire a Foxp3+ Treg cell phenotype in a variety of experimental settings, such as lymphopenia-driven homeostatic expansion [13], [14], [15] and subimmunogenic administration of either free Ag [16], [17], [18], [19], [20] or DEC-205+ dendritic cell-targeted foreign [21], [22], [23], [24] and self-Ag [25], [26]. In addition, the existence of CD4+Foxp3– precursors in lymph nodes (LNs) of non-TCR transgenic, non-manipulated mice that are precommitted to differentiate into Foxp3+ Treg cells has provided evidence on the relevance of peripheral Treg cell induction in the steady state [27]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: CD4(+)CD25(+) regulatory T (Treg) cell lineage commitment and expression of the transcription factor Foxp3 can be induced at the CD4(+)CD8(+) double-positive (DP) and CD4(+)CD8(?) single-positive stages of thymic development, as well as in postthymic CD4(+) T cells in peripheral lymphoid tissues. The availability of transgenic mice with Foxp3-dependent fluorochrome reporter gene expression has greatly facilitated studies on the intra- and extrathymic generation of murine Foxp3(+) Treg cells. Here, we performed a comparative analysis of thymic Treg cell development and peripheral compartments of mature Treg cells in various transgenic strains with gene targeted and bacterial artificial chromosome (BAC)-driven Foxp3-fluorochrome expression. These studies revealed a relative deficiency of Foxp3(+) DP thymocytes selectively in mice with targeted insertion of the fluorochrome reporter gene coding sequence into the endogenous Foxp3 gene. While Foxp3 BAC-driven fluorochrome expression in ex vivo CD4(+) T cells was found to faithfully reflect Foxp3 protein expression, we provide evidence that Foxp3 BAC transgenesis can result in sizable populations of Foxp3(+) Treg cells that lack fluorochrome reporter expression. This could be attributed to both timely delayed up-regulation of BAC expression in developing Treg cells and the accumulation of peripheral Foxp3(+) Treg cells with continuous transcriptional inactivity of the Foxp3 BAC transgene.
    PLoS ONE 08/2012; 7(8):e41971. DOI:10.1371/journal.pone.0041971 · 3.23 Impact Factor
  • Source
    • "Bonifaz et al. showed that proteins targeted to this receptor improve antigen presentation by 100-fold [21]. Further, DEC-205 targeting has been linked with DC ability to induce tolerance in vitro as well as in animal models [28] [29]. Therefore, iDCs can possibly be primed along a tolerogenic pathway through targeting of the DEC-205 receptor. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Microparticulate systems for delivery of therapeutics to DCs for immunotherapy have gained attention recently. However, reports addressing the optimization of DC-targeting microparticle delivery systems are limited, particularly for cases where the goal is to deliver payload to DCs in a non-activating fashion. Here, we investigate targeting DCs using poly (d lactide-co-glycolide) microparticles (MPs) in a non-stimulatory manner and assess efficacy in vitro and in vivo. We modified MPs by surface immobilizing DC receptor targeting molecules - antibodies (anti-CD11c, anti-DEC-205) or peptides (P-D2, RGD), where anti-CD11c antibody, P-D2 and RGD peptides target integrins and anti-DEC-205 antibody targets the c-type lectin receptor DEC-205. Our results demonstrate the modified MPs are neither toxic nor activating, and DC uptake of MPs in vitro is improved by the anti-DEC-205 antibody, the anti-CD11c antibody and the P-D2 peptide modifications. The P-D2 peptide MP modification significantly improved DC antigen presentation in vitro both at immediate and delayed time points. Notably, MP functionalization with P-D2 peptide and anti-CD11c antibody increased the rate and extent of MP translocation in vivo by DCs and MΦs, with the P-D2 peptide modified MPs demonstrating the highest translocation. This work informs the design of non-activating polymeric microparticulate applications such as vaccines for autoimmune diseases.
    Biomaterials 07/2012; 33(29):7221-32. DOI:10.1016/j.biomaterials.2012.06.049 · 8.56 Impact Factor
Show more

We use cookies to give you the best possible experience on ResearchGate. Read our cookies policy to learn more.