Central Role Of Dendritic Cells Research Articles

Eimeria tenella 14-kDa phosphohistidine phosphatase stimulates maturation of chicken dendritic cells and mediates DC-induced T cell priming in a Th1 cytokine interface

Given the central role of dendritic cells (DCs) in directing cell-mediated immunity, this study investigated the capability of Eimeria tenella 14-kDa phosphohistidine phosphatase (EtPHP14) to mature chicken DCs and initiate DC-induced T cell immunity. With the aim of identifying novel protective Eimeria antigen, EtPHP14 gene was successfully cloned and EtPHP14 recombinant protein (rEtPHP14) was expressed in Escherichia coli expression system. rEtPHP14 binding was identified on the surface of chicken DCs by Immunofluorescence assay. DC phenotypes were evaluated by flow cytometry and results indicated that MHCII, CD80, CD86, CD1.1 and CD11c were up-modulated in DCs following rEtPHP14 treatment. RT-qPCR showed increased transcript levels of DC maturation markers CCL5, CCR7 and CD83 in rEtPHP14-treated DCs. Moreover, transcript profile of genes associated with intracellular signaling pathways that characterize the immunogenic (TLR signaling) or tolerogenic (Wnt signaling) state of DCs revealed that TLR signaling was stimulated and Wnt signaling was inhibited in rEtPHP14-treated DCs. Furthermore, proliferation of T cells and differentiation of CD4+ cells were promoted when rEtPHP14-treated DCs were co-cultured with autologous T cells. DCs incubated with rEtPHP14 alone expressed increased IL-12 and IFN-γ levels while IL-10 and TGF-β levels remained unaffected. Likewise, similar trend of IFN-γ expression was noted in rEtPHP14 treated DC-T cell coculture, whereas IL-4 expression remained unchanged. These findings indicate that EtPHP14 is an important molecule that can upregulate host immune response, particularly Th1, during host-parasite interaction, suggesting its importance as a novel candidate for coccidiosis vaccine.

Central Role of Dendritic Cells in Pulmonary Arterial Hypertension in Human and Mice.

The pathogenesis of idiopathic pulmonary arterial hypertension (IPAH) is not fully understood, but evidence is accumulating that immune dysfunction plays a significant role. We previously reported that 31-week-old Tnfaip3DNGR1-KO mice develop pulmonary hypertension (PH) symptoms. These mice harbor a targeted deletion of the TNFα-induced protein-3 (Tnfaip3) gene, encoding the NF-κB regulatory protein A20, specifically in type I conventional dendritic cells (cDC1s). Here, we studied the involvement of dendritic cells (DCs) in PH in more detail. We found various immune cells, including DCs, in the hearts of Tnfaip3DNGR1-KO mice, particularly in the right ventricle (RV). Secondly, in young Tnfaip3DNGR1-KO mice, innate immune activation through airway exposure to toll-like receptor ligands essentially did not result in elevated RV pressures, although we did observe significant RV hypertrophy. Thirdly, PH symptoms in Tnfaip3DNGR1-KO mice were not enhanced by concomitant mutation of bone morphogenetic protein receptor type 2 (Bmpr2), which is the most affected gene in PAH patients. Finally, in human IPAH lung tissue we found co-localization of DCs and CD8+ T cells, representing the main cell type activated by cDC1s. Taken together, these findings support a unique role of cDC1s in PAH pathogenesis, independent of general immune activation or a mutation in the Bmpr2 gene.

REV-ERB mediated regulation of dendritic cell maturation and function

Abstract The REV-ERBs (REV-ERBα and REV-ERBβ) are members of the nuclear receptor superfamily of ligand-regulated transcription factors and owing to their ability to recruit corepressor, act as transcriptional repressors. The REV-ERBs have well-established roles in regulating various physiological functions, including metabolism and the circadian rhythm. However, little is known about their roles in the immune system. While some evidence exists suggesting the REV-ERBs, particularly REV-ERBα, regulates macrophage inflammatory responses, the REV-ERB’s role in regulating other cells of myeloid origin remains largely unknown. Dendritic cells (DCs), like macrophages, are of myeloid origin and serve as the master regulator of immune responses by connecting microbial sensing and innate immunity to adaptive immune responses. Given the central role of DCs in regulating immune responses, we investigated if the REV-ERBs regulate DC maturation and function. We found that both REV-ERBα and REV-ERBβ expression is upregulated during the course of bone marrow derived dendritic cell (BMDCs) differentiation. BMDCs from REV-ERBα and REV-ERBβ deficient mice showed enhanced expression of maturation markers like CD86, MHCII, CD83 and proinflammatory cytokines. In contrast, treatment of BMDCs with a REV-ERB-specific agonist, SR9009, inhibited the expression of these maturation markers and proinflammatory cytokines. Our study suggests the REV-ERBs act as negative regulators of dendritic cell maturation and function thus pharmacological modulation of REV-ERB activity could be an attractive strategy in treating inflammatory diseases.

Dendritic Cell Cancer Therapy: Vaccinating the Right Patient at the Right Time.

Immune checkpoint inhibitors propelled the field of oncology with clinical responses in many different tumor types. Superior overall survival over chemotherapy has been reported in various metastatic cancers. Furthermore, prolonged disease-free and overall survival have been reported in the adjuvant treatment of stage III melanoma. Unfortunately, a substantial portion of patients do not obtain a durable response. Therefore, additional strategies for the treatment of cancer are still warranted. One of the numerous options is dendritic cell vaccination, which employs the central role of dendritic cells in activating the innate and adaptive immune system. Over the years, dendritic cell vaccination was shown to be able to induce an immunologic response, to increase the number of tumor infiltrating lymphocytes and to provide overall survival benefit for at least a selection of patients in phase II studies. However, with the success of immune checkpoint inhibition in several malignancies and considering the plethora of other treatment modalities being developed, it is of utmost importance to delineate the position of dendritic cell therapy in the treatment landscape of cancer. In this review, we address some key questions regarding the integration of dendritic cell vaccination in future cancer treatment paradigms.

Innate immunity in miscarriage and preterm birth:the central role of dendritic cells and invariant natural killer T(iNKT)cells

近年、生殖免疫において自然免疫の重要性が指摘されている。その中で、強力な抗原提示能とサイトカイン産生能を有する樹状細胞(dendritic cells: DCs)や、数は少ないながらも異物に対して迅速且つ大量のサイトカイン、細胞障害性因子を放出するinvariant natural killer T(iNKT)細胞は、流早産発症と深く関与している。本稿では、マウス、ヒト両面から、これら自然免疫担当細胞の役割や炎症を惹起する抗原について考察し、新しい流早産発症メカニズムについての知見を述べる。

Low Concentration of 5-Fluorouracil Increases the Effectiveness of Tumor RNA to Activate Murine Dendritic Cells.

Considering the central role of dendritic cells (DCs) on the development of an antitumor immune response, in this study we used a murine model to evaluate how DC transfection with drug-treated tumor cell RNA changes their phenotype, and whether transfection enhances the in vivo effectiveness of a DC-based antitumor vaccine. MC-38 colorectal tumor cells were pretreated with the minimum effective concentration of 5-fluorouracil (5-FU), then their total RNA was extracted and transfected into DCs. These DCs were inoculated into C57Bl/6 mice bearing subcutaneous MC-38 tumor. DC transfection with drug-treated tumor RNA increases the percentages of CD40+ (from 37.6% to 61.4%), CD86+ (from 39.8% to 53.4%), and major histocompatibility complex class II+ (from 51.2% to 75.3%) cells, whereas significantly increases the in vivo generation of interferon-γ producer lymphocytes. These results reinforce our view that treatment of tumor cells with 5-FU induces transcriptional changes that can be transferred to DCs by RNA transfection, enhancing their ability to stimulate an antitumor response.

CXCL4 Exposure Potentiates TLR-Driven Polarization of Human Monocyte-Derived Dendritic Cells and Increases Stimulation of T Cells.

Chemokines have been shown to play immune-modulatory functions unrelated to steering cell migration. CXCL4 is a chemokine abundantly produced by activated platelets and immune cells. Increased levels of circulating CXCL4 are associated with immune-mediated conditions, including systemic sclerosis. Considering the central role of dendritic cells (DCs) in immune activation, in this article we addressed the effect of CXCL4 on the phenotype and function of monocyte-derived DCs (moDCs). To this end, we compared innate and adaptive immune responses of moDCs with those that were differentiated in the presence of CXCL4. Already prior to TLR- or Ag-specific stimulation, CXCL4-moDCs displayed a more matured phenotype. We found that CXCL4 exposure can sensitize moDCs for TLR-ligand responsiveness, as illustrated by a dramatic upregulation of CD83, CD86, and MHC class I in response to TLR3 and TLR7/8-agonists. Also, we observed a markedly increased secretion of IL-12 and TNF-α by CXCL4-moDCs exclusively upon stimulation with polyinosinic-polycytidylic acid, R848, and CL075 ligands. Next, we analyzed the effect of CXCL4 in modulating DC-mediated T cell activation. CXCL4-moDCs strongly potentiated proliferation of autologous CD4+ T cells and CD8+ T cells and production of IFN-γ and IL-4, in an Ag-independent manner. Although the internalization of Ag was comparable to that of moDCs, Ag processing by CXCL4-moDCs was impaired. Yet, these cells were more potent at stimulating Ag-specific CD8+ T cell responses. Together our data support that increased levels of circulating CXCL4 may contribute to immune dysregulation through the modulation of DC differentiation.

INDUCTION OF T-CELL IMMUNE RESPONSE IN CHRONIC HCV-INFECTED PATIENTS WITH UNDERLYING DENDRITIC CELL IMMUNOTHERAPY

A key role of T cells in viral elimination and absence of strong T cell responses in patients with chronic hepatitis C virus (HCV) infection presumes that activation of antigen-specific T cells may be a promising approach to enhance treatment efficacy. Given the central role of dendritic cells (DCs) in the induction of T cell response, the aim of our study was to evaluate effects of DC immunotherapy upon immunological parameters in chronic HCV infection. Ten patients with chronic hepatitis C (genotype 1) were vaccinated with monocytederived DCs, generated in presence of IFNα (IFN-DCs) and pulsed with recombinant HCV Core (1–120) and NS3 (1192–1457) proteins. The vaccination protocol included as initiating procedure (one injection per week, ns = 4) and maintaining treatment (one monthly injection, ns = 6), with subsequent follow up for 6 months. The immunotherapy was not associated with serious adverse events, significant post-vaccination reactions, or increased hepatitis C activity, according to biochemical tests. Ex vivo studies have shown that immunotherapy elicited strong and stable immune response to Core and moderate response to NS3 protein, which manifested as a significant increase of MNC proliferation and IFNγ production in response to Core and enhancement of IFNγ production (without higher proliferation rates), in response to NS3. DC immunotherapy also led to increase of ConA-induced MNC proliferation up to normal levels indicating a recovery of mitogenic T cell reactivity. Meanwhile, T cell activation did not elicit antigen-specific Th2 response and expansion of CD4 + CD25 + CD127 regulatory T cells. Despite induced immune response, the immunotherapy with DCs was not accompanied by decreased viremia levels. Nevertheless, a transitory decrease of viral load in four patients and stable decrease of viremia in two patients as well as an inverse correlation between NS3-specific proliferation and viremia (Rss = 0.62; p < 0.05) by the end of 6-month follow-up indicated that the antigenspecific T cells may have a potential to control viral replication.

The renal microenvironment modifies dendritic cell phenotype.

Renal dendritic cells are a major component of the renal mononuclear phagocytic system. In the renal interstitium, these cells are exposed to an osmotic gradient, mainly sodium, whose concentration progressively increases towards inner medulla. Renal allograft rejection affects predominantly the cortex, suggesting a protective role of the renal medullary micromilieu. Whether osmolar variations can modulate the function of renal dendritic cells is currently undefined. Considering the central role of dendritic cells in promoting allorejection, we tested whether the biophysical micromilieu, particularly the interstitial osmotic gradient, influences their alloreactivity. There was a progressive depletion of leukocytes towards the medulla of homeostatic kidney. Only macrophages opposed this tendency. Flow cytometry of homeostatic and post-transplant medullary dendritic cells revealed a switch towards a macrophage-like phenotype. Similarly, bone marrow-derived dendritic cells developed ex vivo in sodium chloride-enriched medium acquired a M2-like signature. Microarray analysis of allotransplant dendritic cells posed a medullary downregulation of genes mainly involved in alloantigen recognition. Gene expression profiles of both medullary dendritic cells and bone marrow-derived dendritic cells matured in hyperosmolar medium had an overlap with the macrophage M2 signature. Thus, the medullary environment inhibits an alloimmune response by modulating the phenotype and function of dendritic cells.

Linking immune responses with fibrosis in allergic eye disease.

Here, we explore an emerging theme in the literature, which is the role of dendritic cells in the causation of fibrosis. To fully appreciate this pathway to disease, we also review the most recent literature regarding dendritic cell biology as it pertains to ocular surface tissues. On the basis of this information, we propose a unifying hypothesis for how dendritic cells may cause conjunctival fibrosis in the allergy setting. Work in models of airway remodeling and liver fibrosis has pointed to a potentially central role for dendritic cells in the pathobiology of fibrosis. Indeed, these cells are recognized as the most potent antigen-presenting cells, and as such activate T lymphocytes that are profibrotic under certain conditions. However, recent findings suggest a more direct role for dendritic cells, which opens up the possibility that a similar pathway may be relevant in the causation of conjunctival fibrosis, particularly in allergic eye disease. Conjunctival fibrosis is a serious clinical concern and is associated with chronic inflammation of the ocular surface tissue, such as in allergic eye disease. Dendritic cells are required in mediating allergic disease by activating pathologic T lymphocytes. Recent findings pointing to a central role for dendritic cell in fibrosis may, however, mean that these cells could also be contributing directly to conjunctival fibrosis. If so, furthering our understanding of dendritic cells could lead to the identification of novel and more effective therapeutic strategies to treat this disease.

Phenotype and polarization of autologous T cells by biomaterial-treated dendritic cells

Given the central role of dendritic cells (DCs) in directing T-cell phenotypes, the ability of biomaterial-treated DCs to dictate autologous T-cell phenotype was investigated. In this study, we demonstrate that differentially biomaterial-treated DCs differentially directed autologous T-cell phenotype and polarization, depending on the biomaterial used to pretreat the DCs. Immature DCs (iDCs) were derived from human peripheral blood monocytes and treated with biomaterial films of alginate, agarose, chitosan, hyaluronic acid, or 75:25 poly(lactic-co-glycolic acid) (PLGA), followed by co-culture of these biomaterial-treated DCs and autologous T cells. When autologous T cells were co-cultured with DCs treated with biomaterial film/antigen (ovalbumin, OVA) combinations, different biomaterial films induced differential levels of T-cell marker (CD4, CD8, CD25, CD69) expression, as well as differential cytokine profiles [interferon (IFN)-γ, interleukin (IL)-12p70, IL-10, IL-4] in the polarization of T helper (Th) types. Dendritic cells treated with agarose films/OVA induced CD4+CD25+FoxP3+ (T regulatory cells) expression, comparable to untreated iDCs, on autologous T cells in the DC-T co-culture system. Furthermore, in this co-culture, agarose treatment induced release of IL-12p70 and IL-10 at higher levels as compared with DC treatment with other biomaterial films/OVA, suggesting Th1 and Th2 polarization, respectively. Dendritic cells treated with PLGA film/OVA treatment induced release of IFN-γ at higher levels compared with that observed for co-cultures with iDCs or DCs treated with all other biomaterial films. These results indicate that DC treatment with different biomaterial films has potential as a tool for immunomodulation by directing autologous T-cell responses.

Apoptosis and dysfunction of blood dendritic cells in patients with falciparum and vivax malaria

Malaria causes significant morbidity worldwide and a vaccine is urgently required. Plasmodium infection causes considerable immune dysregulation, and elicitation of vaccine immunity remains challenging. Given the central role of dendritic cells (DCs) in initiating immunity, understanding their biology during malaria will improve vaccination outcomes. Circulating DCs are particularly important, as they shape immune responses in vivo and reflect the functional status of other subpopulations. We performed cross-sectional and longitudinal assessments of the frequency, phenotype, and function of circulating DC in 67 Papuan adults during acute uncomplicated P. falciparum, P. vivax, and convalescent P. falciparum infections. We demonstrate that malaria patients display a significant reduction in circulating DC numbers and the concurrent accumulation of immature cells. Such alteration is associated with marked levels of spontaneous apoptosis and impairment in the ability of DC to mature, capture, and present antigens to T cells. Interestingly, sustained levels of plasma IL-10 were observed in patients with acute infection and were implicated in the induction of DC apoptosis. DC apoptosis was reversed upon IL-10 blockade, and DC function recovered when IL-10 levels returned to baseline by convalescence. Our data provide key information on the mechanisms behind DC suppression during malaria and will assist in developing strategies to better harness DC's immunotherapeutic potential.

Redefining the role of dendritic cells in periodontics

A properly functioning adaptive immune system signifies the best features of life. It is diverse beyond compare, tolerant without fail, and capable of behaving appropriately with a myriad of infections and other challenges. Dendritic cells (DCs) are required to explain how this remarkable system is energized and directed. DCs consist of a family of antigen presenting cells, which are bone-marrow-derived cells that patrol all tissues of the body with the possible exceptions of the brain and testes. DCs function to capture bacteria and other pathogens for processing and presentation to T cells in the secondary lymphoid organs. They serve as an essential link between innate and adaptive immune systems and induce both primary and secondary immune responses. As a result of progress worldwide, there is now evidence of a central role for dendritic cells in initiating antigen-specific immunity and tolerance. This review addresses the origins and migration of DCs to target sites, their basic biology and plasticity in playing a key role in periodontal diseases, and finally, selected strategies being pursued to harness its ability to prevent periodontal diseases.

Abstract B14: Minimum effective concentration of paclitaxel improves the effectivity of dendritic cells transfected with tumor RNA.

Abstract The central role of dendritic cells (DCs) in antigen presentation and induction of antitumor immunity supported the development of antitumor vaccines based on these cells. In previous studies, we have observed that treatment with ultra-low doses of paclitaxel (PAC) modulated human DCs to express the phenotype of mature and activated cells, and stimulated their antigen presentation activity. At the same time, tumor cells treated with low concentrations of drugs became more immunogenic and more susceptible to the lytic activity of cytotoxic T lymphocytes in vitro. Therefore, we aimed to verify if the transfection of DCs with drug-treated tumor cells RNA enhances the effectiveness of DC-based vaccines and if the in vitro effects are reproducible in vivo. Murine colon tumor cells (MC-38) were subcutaneously inoculated in C57Bl/6 mice. At the 10th and 17th days after inoculation, they received a DC vaccine transfected with RNA of MC-38 cells pre-treated with minimum effective concentration of PAC. These DCs expressed 12% higher levels of CD40 and were able to delay the tumor growth when compared with non-treated animals. Although the differences were not significant, our results suggest that the treatment of tumor cells with low concentration of PAC can enhance the immunogenicity of tumor cells, which is transfered for DCs by RNA transfection, and delay tumor growth. Financial support: FAPESP 2009/18331-8; FAPESP 2010/06013-9. Citation Format: Marcela Rodrigues Camargo, Cecília Pessoa Rodrigues, Carolina Mendonça Gorgulho, Fabiana Albani Zambuzi, Victória Elizabeth Galvão, Juliana Cristina Longo Frederico, Marcimara Penitenti, Ramon Kaneno. Minimum effective concentration of paclitaxel improves the effectivity of dendritic cells transfected with tumor RNA. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B14.

Decisions About Dendritic Cells: Past, Present, and Future

A properly functioning adaptive immune system signifies the best features of life. It is diverse beyond compare, tolerant without fail, and capable of behaving appropriately with a myriad of infections and other challenges. Dendritic cells are required to explain how this remarkable system is energized and directed. I frame this article in terms of the major decisions that my colleagues and I have made in dendritic cell science and some of the guiding themes at the time the decisions were made. As a result of progress worldwide, there is now evidence of a central role for dendritic cells in initiating antigen-specific immunity and tolerance. The in vivo distribution and development of a previously unrecognized white cell lineage is better understood, as is the importance of dendritic cell maturation to link innate and adaptive immunity in response to many stimuli. Our current focus is on antigen uptake receptors on dendritic cells. These receptors enable experiments involving selective targeting of antigens in situ and new approaches to vaccine design in preclinical and clinical systems.

Central Role of Dendritic Cells in Shaping the Adaptive Immune Response During Respiratory Syncytial Virus Infection

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract disease in young children. Premature infants, immunocompromised individuals and the elderly exhibit the highest risk for the development of severe RSV-induced disease. Murine studies demonstrate that CD8 T cells mediate RSV clearance from the lungs. Murine studies also indicate that the host immune response contributes to RSV-induced morbidity as T-cell depletion prevents the development of disease despite sustained viral replication. Dendritic cells (DCs) play a central role in the induction of the RSV-specific adaptive immune response. Following RSV infection, lung-resident DCs acquire viral antigens, migrate to the lung-draining lymph nodes and initiate the T-cell response. This article focuses on data generated from both in vitro DC infection studies and RSV mouse models that together have advanced our understanding of how RSV infection modulates DC function and the subsequent impact on the adaptive immune response.

Primed Antigen-Specific CD4+ T Cells Are Required for NK Cell Activation In Vivo upon Leishmania major Infection

The ability of NK cells to rapidly produce IFN-gamma is an important innate mechanism of resistance to many pathogens including Leishmania major. Molecular and cellular components involved in NK cell activation in vivo are still poorly defined, although a central role for dendritic cells has been described. In this study, we demonstrate that Ag-specific CD4(+) T cells are required to initiate NK cell activation early on in draining lymph nodes of L. major-infected mice. We show that early IFN-gamma secretion by NK cells is controlled by IL-2 and IL-12 and is dependent on CD40/CD40L interaction. These findings suggest that newly primed Ag-specific CD4(+) T cells could directly activate NK cells through the secretion of IL-2 but also indirectly through the regulation of IL-12 secretion by dendritic cells. Our results reveal an unappreciated role for Ag-specific CD4(+) T cells in the initiation of NK cell activation in vivo upon L. major infection and demonstrate bidirectional regulations between innate and adaptive immunity.

Ischemic Injury Enhances Dendritic Cell Immunogenicity via TLR4 and NF-κB Activation

Ischemic (isc) injury during the course of transplantation enhances the immunogenicity of allografts and thus results in poorer graft outcome. Given the central role of dendritic cells (DCs) in mounting alloimmune responses, activation of donor DCs by ischemia may have a primary function in the increased immunogenicity of isc allografts. In this study, we sought to investigate the effect of ischemia on DC activity in vitro. Following induction of ischemia, bone marrow-derived DCs were shown to augment allogeneic T cell proliferation as well as the IFN-gamma response. Isc DCs produced greater levels of IL-6, and isc insult was concurrent with NF-kappaB activation. TLR4 ligation was also shown to occur in isc DCs, most likely in response to the endogenous ligand heat shock protein 70, which was found to be elevated in DCs following isc injury, and lack of TLR4 abrogated the observed effects of isc DCs. As compared with control DCs, isc DCs injected into the footpads of mice demonstrated enhanced migration, which was concomitant with increased recipient T cell activity. Moreover, isc DCs underwent a greater degree of apoptosis in the lymph nodes of injected mice, which may further demonstrate enhanced immunogenicity of isc DCs. We thus show that isc injury of DCs enhances DC function, augments the allogeneic T cell response, and occurs via ligation of TLR4, followed by activation of NF-kappaB. These data may serve to identify novel therapeutic targets to attenuate graft immunogenicity following ischemia.

Blocking TH17-polarizing cytokines by histone deacetylase inhibitors in vitro and in vivo

Histone deacetylase (HDAC) inhibitors are small molecules inducing cell-cycle arrest, differentiation, and apoptosis, currently undergoing clinical trials as anticancer drugs. In addition, emerging evidence suggests HDAC inhibitors may have anti-inflammatory and immunomodulatory properties as well, although the molecular mechanisms remain poorly defined. Given the central role of dendritic cells (DC) in the induction and maintenance of the inflammatory and immune response, we investigated the effects of HDAC inhibitors on the maturation and activation of human monocyte-derived DC in the presence of LPS and IFN-gamma. Our results show that the production of T(H)1- and T(H)17-inducing cytokines, namely IL-12 and IL-23, was inhibited by trichostatin A (72% and 52%, respectively) and suberoylanilide hydroxamic acid (86% and 83%). Strikingly, HDAC inhibitors were effective if added simultaneously as well as after the proinflammatory challenge, and their effect was not associated to a reduction of expression or function of LPS/IFN-gamma receptors. These findings were confirmed in two different murine models. In addition, HDAC inhibitors selectively blocked the production of T(H)1-attracting chemokines CXCL9, CXCL10, and CXCL11. The reduction of T(H)1- and T(H)17-inducing cytokines as well as T(H)1-attracting chemokines may represent relevant mechanisms through which HDAC inhibitors at nonproapoptotic doses exert their immunomodulatory properties.

Central role of dendritic cells in the regulation and deregulation of immune responses.

Dendritic cells (DCs) play a critical role in orchestrating the innate and adaptive components of the immune system so that appropriate, coordinated responses are mounted against infectious agents. Tissue-resident DCs interact with microbes through germline-encoded pattern-recognition receptors (PRRs), which recognize molecular patterns expressed by various microorganisms. Antigens use PRR activation to instruct DCs for the appropriate priming of natural killer (NK) cells, followed by specific T-cell responses. Due to the central role of DCs in regulating the activation and progression of immune responses, minor imbalances in the feedback control of Toll-like receptor (TLR)-activated cells have been associated with autoimmunity in genetically prone individuals. We review here recent findings on the role of DCs in the priming of innate and adaptive immune responses and the possible involvement of DCs in inducing and maintaining autoimmune reactions.