Specialized role of migratory dendritic cells in peripheral tolerance induction

The Journal of clinical investigation (Impact Factor: 13.22). 01/2013; 123(2). DOI: 10.1172/JCI65260
Source: PubMed


Harnessing DCs for immunotherapies in vivo requires the elucidation of the physiological role of distinct DC populations. Migratory DCs traffic from peripheral tissues to draining lymph nodes charged with tissue self antigens. We hypothesized that these DC populations have a specialized role in the maintenance of peripheral tolerance, specifically, to generate suppressive Foxp3+ Tregs. To examine the differential capacity of migratory DCs versus blood-derived lymphoid-resident DCs for Treg generation in vivo, we targeted a self antigen, myelin oligodendrocyte glycoprotein, using antibodies against cell surface receptors differentially expressed in these DC populations. Using this approach together with mouse models that lack specific DC populations, we found that migratory DCs have a superior ability to generate Tregs in vivo, which in turn drastically improve the outcome of experimental autoimmune encephalomyelitis. These results provide a rationale for the development of novel therapies targeting migratory DCs for the treatment of autoimmune diseases.

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    • "In murine experimental setups, tolerance induced by LCs has been explained by mechanisms such as induction of Treg (Gomez de Agüero et al, 2012), immunosuppressive IL-10 release (Igyarto et al, 2009), or incomplete maturation (Azukizawa et al, 2011; Shklovskaya et al, 2011). We could not detect production of IL-10 in emigrant LCs, and targeting via Langerin did not yield more antigen-specific Treg than targeting via DEC-205 (Idoyaga et al, 2013). In line with our observations, when OVA expression was induced in keratinocytes, imiquimod-triggered inflammation was not sufficient to prime OT-I-dependent autoimmunity, and this tolerance to OVA was independent of Treg (Holcmann et al, 2009). "
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    ABSTRACT: Skin dendritic cells (DCs) control the immunogenicity of cutaneously administered vaccines. Antigens targeted to DCs via the C-type lectin Langerin/CD207 are cross-presented to CD8+ T cells in vivo. We investigated the relative roles of Langerhans cells (LCs) and Langerin+ dermal DCs (dDCs) in different vaccination settings. Poly(I:C) and anti-CD40 agonist antibody promoted cytotoxic responses upon intradermal immunization with ovalbumin (OVA)-coupled anti-Langerin antibodies (Langerin/OVA). This correlated with CD70 upregulation in Langerin+ dDCs, but not LCs. In chimeric mice where Langerin targeting was restricted to dDCs, CD8+ T-cell memory was enhanced. Conversely, providing Langerin/OVA exclusively to LCs failed to prime cytotoxicity, despite initial antigen cross-presentation to CD8+ T cells. Langerin/OVA combined with imiquimod could not prime CD8+ T cells and resulted in poor cytotoxicity in subsequent responses. This tolerance induction required targeting and maturation of LCs. Altogether, Langerin+ dDCs prime long-lasting cytotoxic responses, while cross-presentation by LCs negatively influences CD8+ T-cell priming. Moreover, this highlights that DCs exposed to TLR agonists can still induce tolerance and supports the existence of qualitatively different DC maturation programs.
    EMBO Molecular Medicine 07/2014; 6(12). DOI:10.15252/emmm.201303283 · 8.67 Impact Factor
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    • "In absence of stimulation at steady-state DCs can induce tolerance. Antigen inoculation in absence of adjuvant leads to T-cell anergy or T-cell deletion (17, 72), and can induce regulatory T cells in the periphery (106–109). Hence, in vivo delivery of antigens to DCs in absence of adjuvant may also be a promising strategy to treat autoimmune disorders as reviewed elsewhere (110). But, to induce immunity rather than tolerance, it is essential to provide the DCs with an activation signal or “adjuvant” in addition to the vaccine antigen. "
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    ABSTRACT: Despite significant effort, the development of effective vaccines inducing strong and durable T-cell responses against intracellular pathogens and cancer cells has remained a challenge. The initiation of effector CD8(+) T-cell responses requires the presentation of peptides derived from internalized antigen on class I major histocompatibility complex molecules by dendritic cells (DCs) in a process called cross-presentation. A current strategy to enhance the effectiveness of vaccination is to deliver antigens directly to DCs. This is done via selective targeting of antigen using monoclonal antibodies directed against endocytic receptors on the surface of the DCs. In this review, we will discuss considerations relevant to the design of such vaccines: the existence of DC subsets with specialized functions, the impact of the antigen intracellular trafficking on cross-presentation, and the influence of maturation signals received by DCs on the outcome of the immune response.
    Frontiers in Immunology 05/2014; 5:255. DOI:10.3389/fimmu.2014.00255
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    • "Interestingly, LN-resident, but not migratory, cDCs have also been reported to sample follicular dendritic cell (FDC)retained Ags (McCloskey et al., 2011). LN-resident cDCs might be important to maintain peripheral tolerance; however, recent experiments suggest that at least under certain conditions, migratory DCs are superior in this respect (Idoyaga et al., 2013). Surprisingly, LN-resident cDCs also seem to control LN entry of lymphocytes by modulating the maturation state of high endothelial venules (Moussion and Girard, 2011), which suggests cDC interactions with stromal components, an area that clearly needs further exploration. "
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    ABSTRACT: Classical dendritic cells (cDCs) form a critical interface between innate and adaptive immunity. As myeloid immune cell sentinels, cDCs are specialized in the sensing of pathogen challenges and cancer. They translate the latter for T cells into peptide form. Moreover, cDCs provide additional critical information on the original antigen context to trigger a diverse spectrum of appropriate protective responses. Here we review recent progress in our understanding of cDC subsets in mice. We will discuss cDC subset ontogeny and transcription factor dependencies, as well as emerging functional specializations within the cDC compartment in lymphoid and nonlymphoid tissues.
    Immunity 05/2014; 40(5):642-656. DOI:10.1016/j.immuni.2014.04.016 · 21.56 Impact Factor
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