Specialized role of migratory dendritic cells in peripheral tolerance induction
01 Feb 2013-Journal of Clinical Investigation (American Society for Clinical Investigation)-Vol. 123, Iss: 2, pp 844-854
TL;DR: It is found that migratory DCs have a superior ability to generate Tregs in vivo, which in turn drastically improve the outcome of experimental autoimmune encephalomyelitis, providing a rationale for the development of novel therapies targeting migratoryDCs for the treatment of autoimmune diseases.
Abstract: 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.
Citations
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TL;DR: Advances in resolution of phenotype and gene expression facilitate the integration of mouse and human immunology, support efforts to unravel human DC function in vivo and continue to present new translational opportunities to medicine.
Abstract: Dendritic cells (DC) are a class of bone-marrow-derived cells arising from lympho-myeloid haematopoiesis that form an essential interface between the innate sensing of pathogens and the activation of adaptive immunity. This task requires a wide range of mechanisms and responses, which are divided between three major DC subsets: plasmacytoid DC (pDC), myeloid/conventional DC1 (cDC1) and myeloid/conventional DC2 (cDC2). Each DC subset develops under the control of a specific repertoire of transcription factors involving differential levels of IRF8 and IRF4 in collaboration with PU.1, ID2, E2-2, ZEB2, KLF4, IKZF1 and BATF3. DC haematopoiesis is conserved between mammalian species and is distinct from monocyte development. Although monocytes can differentiate into DC, especially during inflammation, most quiescent tissues contain significant resident populations of DC lineage cells. An extended range of surface markers facilitates the identification of specific DC subsets although it remains difficult to dissociate cDC2 from monocyte-derived DC in some settings. Recent studies based on an increasing level of resolution of phenotype and gene expression have identified pre-DC in human blood and heterogeneity among cDC2. These advances facilitate the integration of mouse and human immunology, support efforts to unravel human DC function in vivo and continue to present new translational opportunities to medicine.
758 citations
TL;DR: Recent progress in the understanding of cDC subset ontogeny and transcription factor dependencies are reviewed, as well as emerging functional specializations within the cDC compartment in lymphoid and nonlymphoid tissues are discussed.
650 citations
Cites background from "Specialized role of migratory dendr..."
...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)....
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...After phagocytosis of intranasally applied Ags, lung cDCs migrate to the draining LN in a CCR7dependent manner and participate in the induction of T cell tolerance over innocuous Ag (Idoyaga et al., 2013)....
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...Interestingly, migratory dermal cDCs rather than LN-resident cDCs seem critical for peripheral tolerance induction (Idoyaga et al., 2013; Tamoutounour et al., 2013)....
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TL;DR: Recent findings that highlight the complex regulatory networks that control skin immunity are discussed, and new paradigms for the mechanisms that regulate skin immune responses in host defence and in chronic inflammation are provided.
Abstract: Immune responses in the skin are important for host defence against pathogenic microorganisms However, dysregulated immune reactions can cause chronic inflammatory skin diseases Extensive crosstalk between the different cellular and microbial components of the skin regulates local immune responses to ensure efficient host defence, to maintain and restore homeostasis, and to prevent chronic disease In this Review, we discuss recent findings that highlight the complex regulatory networks that control skin immunity, and we provide new paradigms for the mechanisms that regulate skin immune responses in host defence and in chronic inflammation
644 citations
TL;DR: What has been learned thus far about human DC biology from clinical studies are discussed, and how current approaches to apply DC vaccines in the clinic could be improved to enhance anti-tumor immunity are discussed.
Abstract: Immunotherapy using dendritic cell (DC)-based vaccination is an approved approach for harnessing the potential of a patient's own immune system to eliminate tumor cells in metastatic hormone-refractory cancer. Overall, although many DC vaccines have been tested in the clinic and proven to be immunogenic, and in some cases associated with clinical outcome, there remains no consensus on how to manufacture DC vaccines. In this review we will discuss what has been learned thus far about human DC biology from clinical studies, and how current approaches to apply DC vaccines in the clinic could be improved to enhance anti-tumor immunity.
495 citations
TL;DR: This Review focuses on recent advances that have succeeded in discriminating DCs from macrophages in the skin, based on ontogeny and global gene-expression profiles, and discusses how this has enabled researchers to revisit the origin, diversity and T cell-stimulatory properties of these cells.
Abstract: Recent studies of ontogeny and gene expression have enabled the discrimination of dendritic cell and macrophage subsets in mouse skin and the identification of their human counterparts, which has led to a growing appreciation of the functional specialization of these subsets.
395 citations
References
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TL;DR: An antigen delivery system targeting these specialized antigen presenting cells in vivo using a monoclonal antibody to a DC-restricted endocytic receptor is devised, which concludes that in the absence of additional stimuli DCs induce transient antigen-specific T cell activation followed by T cell deletion and unresponsiveness.
Abstract: Dendritic cells (DCs) have the capacity to initiate immune responses, but it has been postulated that they may also be involved in inducing peripheral tolerance. To examine the function of DCs in the steady state we devised an antigen delivery system targeting these specialized antigen presenting cells in vivo using a monoclonal antibody to a DC-restricted endocytic receptor, DEC-205. Our experiments show that this route of antigen delivery to DCs is several orders of magnitude more efficient than free peptide in complete Freund's adjuvant (CFA) in inducing T cell activation and cell division. However, T cells activated by antigen delivered to DCs are not polarized to produce T helper type 1 cytokine interferon γ and the activation response is not sustained. Within 7 d the number of antigen-specific T cells is severely reduced, and the residual T cells become unresponsive to systemic challenge with antigen in CFA. Coinjection of the DC-targeted antigen and anti-CD40 agonistic antibody changes the outcome from tolerance to prolonged T cell activation and immunity. We conclude that in the absence of additional stimuli DCs induce transient antigen-specific T cell activation followed by T cell deletion and unresponsiveness.
1,903 citations
"Specialized role of migratory dendr..." refers background or methods in this paper
...In contrast, delivery of antigen to steady-state DCs using α-DEC mAbs can lead to tolerance through deletion (26, 27) and/or the generation of Tregs (23, 39, 40), but it was suggested that CD8+ lymphoidresident DCs mediated Treg conversion (41)....
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...After α-receptor–MOGp mAb inoculation in steady state, MOG-specific CD4+ T cells lacking Foxp3 expression peaked on days 4–7, but rapidly declined thereafter (Supplemental Figure 5B), probably by deletion/cell death (26, 27)....
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TL;DR: Gene expression analysis showed that IL-2 signaling was required for maintenance of the expression of genes involved in the regulation of cell growth and metabolism, which seems to be critically required for maintaining the homeostasis and competitive fitness of Treg cells in vivo.
Abstract: Regulatory T cells (T(reg) cells) expressing the forkhead family transcription factor Foxp3 are critical mediators of dominant immune tolerance to self. Most T(reg) cells constitutively express the high-affinity interleukin 2 (IL-2) receptor alpha-chain (CD25); however, the precise function of IL-2 in T(reg) cell biology has remained controversial. To directly assess the effect of IL-2 signaling on T(reg) cell development and function, we analyzed mice containing the Foxp3(gfp) knock-in allele that were genetically deficient in either IL-2 (Il2(-/-)) or CD25 (Il2ra(-/-)). We found that IL-2 signaling was dispensable for the induction of Foxp3 expression in thymocytes from these mice, which indicated that IL-2 signaling does not have a nonredundant function in the development of T(reg) cells. Unexpectedly, Il2(-/-) and Il2ra(-/-) T(reg) cells were fully able to suppress T cell proliferation in vitro. In contrast, Foxp3 was not expressed in thymocytes or peripheral T cells from Il2rg(-/-) mice. Gene expression analysis showed that IL-2 signaling was required for maintenance of the expression of genes involved in the regulation of cell growth and metabolism. Thus, IL-2 signaling seems to be critically required for maintaining the homeostasis and competitive fitness of T(reg) cells in vivo.
1,765 citations
"Specialized role of migratory dendr..." refers methods in this paper
...or α-Langerin–MOGp (Supplemental Figure 3B), we co-transferred MOG-specif ic naive T cells as a source for IL-2 (24, 25), along with MOG-specific Foxp3-EGFP+ nTregs (Figure 2C)....
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...Since MOG-specific Foxp3+ nTregs proliferated minimally in response to control Ig–, α-DEC–, or α-Langerin–MOGp (Supplemental Figure 3B), we co-trans- ferred MOG-specif ic naive T cells as a source for IL-2 (24, 25), along with MOG-specific Foxp3-EGFP+ nTregs (Figure 2C)....
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TL;DR: It is suggested that self-reactive T cells are continuously suppressed by Treg cells and that when suppression is relieved, self- reactive T cells become activated and facilitate accelerated maturation of dendritic cells.
Abstract: Mice lacking the transcription factor Foxp3 (Foxp3(-)) lack regulatory T (T(reg)) cells and develop fatal autoimmune pathology. In Foxp3(-) mice, many activated effector T cells express self-reactive T cell receptors that are expressed in T(reg) cells in wild-type mice. Thus, in wild-type mice, most self-reactive thymocytes escaping negative selection are diverted into the T(reg) lineage, and whether T(reg) cells are critical in self-tolerance in wild-type mice remains unknown. Here, acute in vivo ablation of T(reg) cells demonstrated a vital function for T(reg) cells in neonatal and adult mice. We suggest that self-reactive T cells are continuously suppressed by T(reg) cells and that when suppression is relieved, self-reactive T cells become activated and facilitate accelerated maturation of dendritic cells.
1,625 citations
TL;DR: DEC-205 provides an efficient receptor-based mechanism for dendritic cells to process proteins for MHC class I presentation in vivo, leading to tolerance in the steady state and immunity after DC maturation.
Abstract: To identify endocytic receptors that allow dendritic cells (DCs) to capture and present antigens on major histocompatibility complex (MHC) class I products in vivo, we evaluated DEC-205, which is abundant on DCs in lymphoid tissues. Ovalbumin (OVA) protein, when chemically coupled to monoclonal αDEC-205 antibody, was presented by CD11c+ lymph node DCs, but not by CD11c− cells, to OVA-specific, CD4+ and CD8+ T cells. Receptor-mediated presentation was at least 400 times more efficient than unconjugated OVA and, for MHC class I, the DCs had to express transporter of antigenic peptides (TAP) transporters. When αDEC-205:OVA was injected subcutaneously, OVA protein was identified over a 4–48 h period in DCs, primarily in the lymph nodes draining the injection site. In vivo, the OVA protein was selectively presented by DCs to TCR transgenic CD8+ cells, again at least 400 times more effectively than soluble OVA and in a TAP-dependent fashion. Targeting of αDEC-205:OVA to DCs in the steady state initially induced 4–7 cycles of T cell division, but the T cells were then deleted and the mice became specifically unresponsive to rechallenge with OVA in complete Freund's adjuvant. In contrast, simultaneous delivery of a DC maturation stimulus via CD40, together with αDEC-205:OVA, induced strong immunity. The CD8+ T cells responding in the presence of agonistic αCD40 antibody produced large amounts of interleukin 2 and interferon γ, acquired cytolytic function in vivo, emigrated in large numbers to the lung, and responded vigorously to OVA rechallenge. Therefore, DEC-205 provides an efficient receptor-based mechanism for DCs to process proteins for MHC class I presentation in vivo, leading to tolerance in the steady state and immunity after DC maturation.
1,379 citations
"Specialized role of migratory dendr..." refers background or methods in this paper
...In contrast, delivery of antigen to steady-state DCs using α-DEC mAbs can lead to tolerance through deletion (26, 27) and/or the generation of Tregs (23, 39, 40), but it was suggested that CD8+ lymphoidresident DCs mediated Treg conversion (41)....
[...]
...After α-receptor–MOGp mAb inoculation in steady state, MOG-specific CD4+ T cells lacking Foxp3 expression peaked on days 4–7, but rapidly declined thereafter (Supplemental Figure 5B), probably by deletion/cell death (26, 27)....
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