Dendritic Cell Immunogenicity Is Regulated by Peroxisome Proliferator-Activated Receptor γ (original) (raw)
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Regulatory dendritic cells: there is more than just immune activation
Frontiers in Immunology, 2012
The immune system exists in a delicate equilibrium between inflammatory responses and tolerance. This unique feature allows the immune system to recognize and respond to potential threats in a controlled but normally limited fashion thereby preventing a destructive overreaction against healthy tissues. While the adaptive immune system was the major research focus concerning activation vs. tolerance in the immune system more recent findings suggest that cells of the innate immune system are important players in the decision between effective immunity and induction of tolerance or immune inhibition. Among immune cells of the innate immune system dendritic cells (DCs) have a special function linking innate immune functions with the induction of adaptive immunity. DCs are the primary professional antigen presenting cells (APCs) initiating adaptive immune responses. They belong to the hematopoietic system and arise from CD34 + stem cells in the bone marrow. Particularly in the murine system two major subgroups of DCs, namely myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) can be distinguished. DCs are important mediators of innate and adaptive immunity mostly due to their remarkable capacity to present processed antigens via major histocompatibility complexes (MHC) to T cells and B cells in secondary lymphoid organs. A large body of literature has been accumulated during the last two decades describing which role DCs play during activation of T cell responses but also during the establishment and maintenance of central tolerance . While the concept of peripheral tolerance has been clearly established during the last years, the role of different sets of DCs and their particular molecular mechanisms of immune deviation has not yet fully been appreciated. In this review we summarize accumulating evidence about the role of regulatory DCs in situations where the balance between tolerance and immunogenicity has been altered leading to pathologic conditions such as chronic inflammation or malignancies.
There is increasing evidence that dendritic cell (DC) immunogenicity is not only positively regulated by ligands of pattern recognition receptors, but also negatively by signals that prevent DC activation and full functional maturation. Depending on their activation status, DCs can induce either immunity or tolerance. In this study, we provide molecular evidence that the transcription factor peroxisome proliferator-activated receptor ␥ (PPAR␥) is a negative regulator of DC maturation and function. Sustained PPAR␥ activation in murine DCs reduced maturation-induced expression of costimulatory molecules and IL-12, and profoundly inhibited their capacity to prime naive CD4 ؉ T cells in vitro. Using PPAR␥-deficient DCs, generated by Cre-mediated ablation of the PPAR␥ gene, agonist-mediated suppression of maturation-induced functional changes were abrogated. Moreover, absence of PPAR␥ increased DC immunogenicity, suggesting a constitutive regulatory function of PPAR␥ in DCs. Adoptive transfer of PPAR␥-activated Ag-presenting DCs induced CD4 ؉ T cell anergy, characterized by impaired differentiation resulting in absent Th1 and Th2 cytokine production and failure of secondary clonal expansion upon restimulation. Collectively, our data support the notion that PPAR␥ is an efficient regulator of DC immunogenicity that may be exploited to deliberately target CD4 ؉ T cell-mediated immune responses.
Dendritic Cells are Both Targets and Initiators of Peripheral Immune Tolerance to Self
2013
Mucin 1 (MUC1) is a highly glycosylated membrane-bound protein normally expressed on the apical surface of ductal epithelial cells. During malignant transformation MUC1 acts as a Tumor-Associated Antigen (TAA) by virtue of its overexpression, loss of polarity, and hypoglycosylation, allowing for T cell and antibody recognition of cryptic peptide epitopes derived from its extracellular domain. Almost all adenocarcinomas express abnormal MUC1 making it an attractive target for cancer vaccines. However, vaccination of MUC1.Tg mice with a synthetic, unglycosylated MUC1 peptide (MUC1p) that mimics one tumor form of the molecule results in a weak anti-MUC1p immune response. WT mice receiving the same vaccine generate robust immunity to MUC1p, suggesting that it is viewed as a "self" antigen in MUC1.Tg mice, and apparently subject to peripheral tolerance. To globally query these distinct programs of immunity and tolerance induced by MUC1p in WT and MUC1.Tg mice respectively, we conducted whole transcriptome analysis of splenic RNA 24h and 72h after i.v. immunization of both mouse strains with MUC1p. We found that a new cohort of "pancreatic" enzymes (e.g. trypsin and CPB1) were expressed by splenic dendritic cells (DC) and regulated such that immunization with self-antigen suppressed their expression while foreign-antigens induced it within 24h post-vaccination. The relative expression of trypsin and CPB1 was highly correlated with the immunogenicity of the DC. Suppressed expression marked DC that were highly tolerized as demonstrated by low costimulatory molecule expression, limited motility, production of Aldh1/2, and preferential priming of naïve CD4 + T cells into Foxp3 + Treg versus IFNγ + cells, while enhanced expression identified immunogenic DC. Deficient NFκβ pathway activation and enhanced STAT3 phosphorylation transcriptionally underlie tolerized DC along v with sustained expression of zDC. Trypsin was required for efficient degradation of the extracellular matrix, while CPB1 was required by DC to induce optimal, antigen-specific proliferation of CD4 + T cells. Importantly, these vaccine-induced changes in DC phenotype affected the entire splenic DC compartment, revealing an underappreciated role for endogenous DC in the transmission and amplification of vaccine-induced immunity or tolerance. These results underscore the importance of vaccine antigen choice and will contribute to rational vaccine design. vi TABLE OF CONTENTS
CCL19 and CCL21 Induce a Potent Proinflammatory Differentiation Program in Licensed Dendritic Cells
Immunity, 2005
stage that is specialized for antigen capture (Steinman, Manfred Kopf, 2 and Martin F. Bachmann 1, * 1991). After uptake of antigen by phagocytosis, via 1 Cytos Biotechnology AG macropinocytosis or via receptor-mediated endocyto-Wagistrasse 25 sis (Albert et al., 1998; Sallusto et al., 1995), the antigen 8952 Zü rich-Schlieren is processed and peptides thereof are presented on the Switzerland cell surface associated with the MHC class I or II mole-2 Molecular Biomedicine cules. After receiving maturation-inducing signals, either Department of Environmental Sciences directly from pathogens or via inflammatory stimuli, Swiss Federal Institute of Technology DCs change the expression pattern of chemokine re-CH-8092 Zurich ceptors, allowing them to leave the peripheral tissue Switzerland and to migrate to draining lymphoid organs (Rescigno 3 Department of Medicine et al., 1999). Upregulation of CCR7 during maturation Duke University Medical Center renders DCs sensitive to two chemoattractants, ELC/ Box 3623 CCL19 and SLC/CCL21, which direct their migration to Durham, North Carolina 27710 T cell regions of lymphoid organs (Cyster, 1999; Sallusto and Lanzavecchia, 2000). Within these regions, DCs can induce both activation and proliferation of Summary specific CTLs and Th cells via presentation of immunogenic peptides in association with MHC class I and II Dendritic cells (DCs) are key instigators of adaptive molecules, respectively. In addition to protection against immune responses. Using an alphaviral expression pathogens, DCs also appear to be central to the regulacloning technology, we have identified the chemokine tion, maturation, and maintenance of cellular immune CCL19 as a potent inducer of T cell proliferation in a responses against cancer (Gunzer et al., 2001; Timmer-DC-T cell coculture system. Subsequent studies showed man and Levy, 1999). Recently, it has emerged that DCs that CCL19 enhanced T cell proliferation by inducing not only induce T cell responses but are equally impormaturation of DCs, resulting in upregulation of costitant for the maintenance of peripheral T cell tolerance mulatory molecules and the production of proinflambecause resting DCs induce T cell tolerance rather than matory cytokines. Moreover, CCL19 programmed DCs immunity (Bonifaz et al., 2002; Probst et al., 2003). for the induction of T helper type (Th) 1 rather than Thus, regulation of DC activation is critical for the es-Th2 responses. Importantly, only activated DCs that tablishment of protective T cell responses as well as migrated from the periphery to draining lymph nodes, for the maintenance of T cell tolerance (for review, see but not resting steady-state DCs residing within (Bachmann and Kopf, 2002)). lymph nodes, expressed high levels of CCR7 in vivo Pathogen-mediated DC activation is usually transand responded to CCL19 with the production of proinduced via the Toll-like receptor (TLR) family (Akira, flammatory cytokines. Migrating DCs isolated from 2001; Beutler, 2002; Medzhitov and Janeway, 2000). mice genetically deficient in CCL19 and CCL21 (plt/ TLR recognize invariable patterns associated with plt) presented an only partially mature phenotype, pathogens like peptidoglycans (TLR2) (Takeuchi et al., highlighting the importance of these chemokines for 1999), double-stranded RNA (TLR3) (Alexopoulou et full DC maturation in vivo. Our findings indicate that al., 2001), LPS (TLR4) (Hoshino et al., 1999; Poltorak CCL19 and CCL21 are potent natural adjuvants for et al., 1998), flagellin (TLR5) (Hayashi et al., 2001), and terminal activation of DCs and suggest that chemobacterial RNA (TLR 7/8) (Diebold et al., 2004; Heil et al., kines not only orchestrate DC migration but also reg-2004) or DNA (TLR9) (Hemmi et al., 2000; Schnare et ulate their immunogenic potential for the induction of al., 2000). Activation of dendritic cells is also induced T cell responses. by proinflammatory cytokines and in particular by members of the TNF superfamily, including TNF-α, Introduction CD40L, and Trance/RANKL (Bachmann et al., 1999; Cella et al., 1996; Koch et al., 1996; Wong et al., 1999). Dendritic cells (DCs) are key initiators of innate and Recently, chemokine receptors have also been shown adaptive immunity (for review, see Banchereau et al., to be directly involved in induction of DC maturation. 2000; Lanzavecchia and Sallusto, 2001; Mellman and Specifically, activation through CCR5 by T. gondii-Steinman, 2001). They are potent antigen-processing derived cyclophilin led to production of high levels of and-presenting cells with the unique ability to stimu-IL-12 in DCs (Aliberti et al., 2000; Aliberti et al., 2003). The importance of DC maturation for the generation of protective T cell responses is also highlighted by the
Frontiers in Immunology, 2012
The last decades of Nobel prize-honored research have unequivocally proven a key role of dendritic cells (DCs) at controlling both T cell immunity and tolerance. A tight balance between these opposing DC functions ensures immune homeostasis and host integrity. Its perturbation could explain pathological conditions such as the attack of self tissues, chronic infections, and tumor immune evasion. While recent insights into the complex DC network help to understand the contribution of individual DC subsets to immunity, the tolerogenic functions of DCs only begin to emerge. As these consist of many different layers, the definition of a "tolerogenic DC" is subjected to variation. Moreover, the implication of DCs and DC subsets in the suppression of autoimmunity are incompletely resolved. In this review, we point out conceptual controversies and dissect the various layers of DC-mediated T cell tolerance. These layers include central tolerance, Foxp3 + regulatory T cells (Tregs), anergy/deletion and negative feedback regulation. The mode and kinetics of antigen presentation is highlighted as an additional factor shaping tolerance. Special emphasis is given to the interaction between layers of tolerance as well as their differential regulation during inflammation. Furthermore, potential technical caveats of DC depletion models are considered. Finally, we summarize our current understanding of DC-mediated tolerance and its role for the suppression of autoimmunity. Understanding the mechanisms of DC-mediated tolerance and their complex interplay is fundamental for the development of selective therapeutic strategies, e.g., for the modulation of autoimmune responses or for the immunotherapy of cancer.