Harnessing dendritic cells in inflammatory skin diseases

The skin immune system harbors a complex network of dendritic cells (DCs). Recent studies highlight a diverse functional specialization of skin DC subsets. In addition to generating cellular and humoral immunity against pathogens, skin DCs are involved in tolerogenic mechanisms to ensure the maintenance of immune homeostasis, as well as in pathogenesis of chronic inflammation in the skin when excessive immune responses are initiated and unrestrained. Harnessing DCs by directly targeting DC-derived molecules or selectively modulate DC subsets is a convincing strategy to tackle inflammatory skin diseases. In this review we discuss recent advances underlining the functional specialization of skin DCs and discuss the potential implication for future DC-based therapeutic strategies.     

Dendritic cell subsets in health and disease

Summary:  The dendritic cell (DC) system of antigen-presenting cells controls immunity and tolerance. DCs initiate and regulate immune responses in a manner that depends on signals they receive from microbes and their cellular environment. They allow the immune system to make qualitatively distinct responses against different microbial infections. DCs are composed of subsets that express different microbial receptors and express different surface molecules and cytokines. Our studies lead us to propose that interstitial (dermal) DCs preferentially activate humoral immunity, whereas Langerhans cells preferentially induce cellular immunity. Alterations of the DC system result in diseases such as autoimmunity, allergy, and cancer. Conversely, DCs can be exploited for vaccination, and novel vaccines that directly target DCs in vivo are being designed.     

Dendritic cells and vaccine design for sexually-transmitted diseases

Dendritic cells (DCs) are major antigen presenting cells (APCs) that can initiate and control host immune responses toward either immunity or tolerance. These features of DCs, as immune orchestrators, are well characterized by their tissue localizations as well as by their subset-dependent functional specialties and plasticity. Thus, the level of protective immunity to invading microbial pathogens can be dependent on the subsets of DCs taking up microbial antigens and their functional plasticity in response to microbial products, host cellular components and the cytokine milieu in the microenvironment.Vaccines are the most efficient and cost-effective preventive medicine against infectious diseases. However, major challenges still remain for the diseases caused by sexually-transmitted pathogens, including HIV, HPV, HSV and Chlamydia. We surmise that the establishment of protective immunity in the female genital mucosa, the major entry and transfer site of these pathogens, will bring significant benefit for the protection against sexually-transmitted diseases. Recent progresses made in DC biology suggest that vaccines designed to target proper DC subsets may permit us to establish protective immunity in the female genital mucosa against sexually-transmitted pathogens.     

Migration of murine intestinal dendritic cell subsets upon intrinsic and extrinsic TLR3 stimulation

Initiation of adaptive immunity to particulate antigens in lymph nodes largely depends on their presentation by migratory dendritic cells (DCs). DC subsets differ in their capacity to induce specific types of immunity, allowing subset-specific DC-targeting to influence vaccination and therapy outcomes. Faithful drug design, however, requires exact understanding of subset-specific versus global activation mechanisms. cDC1, the subset of DCs that excel in supporting immunity toward viruses, intracellular bacteria, and tumors, express uniquely high levels of the pattern recognition receptor TLR3. Using various murine genetic models, we show here that both, the cDC1 and cDC2 subsets of cDCs are activated and migrate equally well in response to TLR3 stimulation in a cell extrinsic and TNF-α dependent manner, but that cDC1 show a unique requirement for type I interferon signaling. Our findings reveal common and differing pathways regulating DC subset migration, offering important insights for the design of DC-based vaccination and therapy approaches.     

Restoration of innate immune activation accelerates Th1‐cell priming and protection following pulmonary mycobacterial infection

The immune mechanisms underlying delayed induction of Th1‐type immunity in the lungs following pulmonary mycobacterial infection remain poorly understood. We have herein investigated the underlying immune mechanisms for such delayed responses and whether a selected innate immune‐modulating strategy can accelerate Th1‐type responses. We have found that, in the early stage of pulmonary infection with attenuated Mycobacterium tuberculosis (M.tb H37Ra), the levels of infection in the lung continue to increase logarithmically until days 14 and 21 postinfection in C57BL/6 mice. The activation of innate immune responses, particularly DCs, in the lung is delayed. This results in a delay in the subsequent downstream immune responses including the migration of antigen‐bearing DCs to the draining lymph node (dLN), the Th1‐cell priming in dLN, and the recruitment of Th1 cells to the lung. However, single lung mucosal exposure to the TLR agonist FimH postinfection is able to accelerate protective Th1‐type immunity via facilitating DC migration to the lung and draining lymph nodes, enhancing DC antigen presentation and Th1‐cell priming. These findings hold implications for the development of immunotherapeutic and vaccination strategies and suggest that enhancement of early innate immune activation is a viable option for improving Th1‐type immunity against pulmonary mycobacterial diseases.     

Dendritic cells and aging: consequences for autoimmunity

The immune system has evolved to mount immune responses against foreign pathogens and to remain silent against self-antigens. A balance between immunity and tolerance is required as any disturbance may result in chronic inflammation or autoimmunity. Dendritic cells (DCs) actively participate in maintaining this balance. Under steady-state conditions, DCs remain in an immature state and do not mount an immune response against circulating self-antigens in the periphery, which maintains a state of tolerance. By contrast, foreign antigens result in DC maturation and DC-induced T-cell activation. Inappropriate maturation of DCs due to infections or tissue injury may cause alterations in the balance between the tolerogenic and immunogenic functions of DCs and instigate the development of autoimmune diseases. This article provides an overview of the effects of advancing age on DC functions and their implications in autoimmunity.     

Functional modulation of dendritic cells to suppress adaptive immune responses

In recent years, dendritic cells (DCs) have entered the center court of immune regulation. Dependent on their ontogeny, state of differentiation, and maturation and thereby a variable expression of membrane-bound and soluble molecules, DCs can induce immunostimulatory as well as immunoregulatory responses. This dual function has made them potential targets in vaccine development in cancer and infections as well as for the prevention and treatment of allograft rejection and autoimmune diseases. The present review is focused on the effect of immune-modulatory factors, such as cytokines and immunosuppressive drugs, and on the survival, differentiation, migration, and maturation of DC human subsets. A better understanding of DC immunobiology may lead to the development of specific therapies to prevent or dampen immune responses.     

Crosstalk between dendritic cell subsets and implications for dendritic cell-based anticancer immunotherapy

Dendritic cells (DCs) are a family of professional antigen-presenting cells that have an indispensable role in the initiation of innate and adaptive immune responses against pathogens and tumor cells. The DC family is very heterogeneous. Two main types of naturally occurring DCs circulate in peripheral blood, each with its unique phenotypic and functional characteristics: myeloid DCs and plasmacytoid. There is an ample number of studies that have focused on the bi-directional crosstalk between DCs and natural killer cells or T cells. However, the crosstalk among the different DC subsets, in the context of infectious diseases and cancer, has until now not received much attention. Here, we review all available literature that has dealt with the crosstalk between plasmacytoid and myeloid DCs and the potential mode of action. Emphasis will be given to the therapeutic potential of the combination of DC subsets for DC-based immunotherapy.     

The Plasticity of γδ T Cells： Innate Immunity,Antigen Presentation and New Immunotherapy

Several signals influence dendritic cell （DC） functions and consequent the immune responses to infectious pathogens. Our recent findings provide a new model of intervention on DCs implicating human γδ T cell stimuli. Vγ/9Vδ2 T cells represent the major subset of circulating human γδ T cells and can be activated by non-peptidic molecules derived from different microorganisms or abnormal metabolic routes. With activated-Vγ/9Vδ2 T cell co-culture, immature DCs acquire features of mature DCs, such as increasing the migratory activity, up-regulating the chemokine receptors, and triggering the Thl immune response. Similar to the NK-derived signals, DC activation is mediated by soluble factors as well as cell-to-cell contact. Many non-peptidic molecules including nitrogen- containing bisphosphonates and pyrophosphomonoester drugs, can stimulate the activity of Vγ/9Vδ2 T cells in vitro and in vivo. The relatively low in vivo toxicity of many of these drugs makes possible novel vaccine and immune-based strategies against infectious diseases.     

Dendritic cells and the immunopathogenesis of systemic lupus erythematosus

Over the last decade, the role of dendritic cells (DCs) in the immunopathogenesis of systemic lupus erythematosus (SLE) has become apparent. As unique mediators of both tolerance and immunity, aberrant myeloid and plasmacytoid DC function can promote autoimmune responses via a number of mechanisms and proinflammatory pathways. This review provides an overview of DC function, the potential role of DCs in promoting autoimmune responses in SLE, and how other abnormalities in lupus can lead to an enhanced engagement of DCs in immune responses. How medications used to treat SLE and other autoimmune conditions may exert effects on DCs is also explored.     

Dendritic cells in the tumor microenvironment: prognostic and theranostic impact

Among all immune cells, dendritic cells (DC) are the most potent APCs in the immune system and are central players of the adaptive immune response. There are phenotypically and functionally distinct DC populations derived from blood and lymphoid organ including plasmacytoid DC (pDC), conventional DC (cDC1 and cDC2) and monocyte-derived DC (moDC). The interaction between these different DCs and tumors is a dynamic process where DC-mediated cross-priming of tumor specific T cells is critical in initiating and sustaining anti-tumor immunity. Their presence within the tumor tends to induce T cell responses and to reduce cancer progression and is associated with improved patient survival. This review will focus on the distinct tumor-associated DCs (TADC) subsets in the tumor microenvironment (TME), their roles in tumor immunology and their prognostic and/or predictive impact in human cancers. The development of therapeutic immunity strategies targeting TADC is promising to enhance their immune-stimulatory capacity in cancers and improve the efficacy of current immunotherapies including immune checkpoint inhibitor (ICI) blockade and DC-based therapies.     

Factors and signals that govern the migration of dendritic cells via lymphatics: recent advances

Dendritic cell (DC) migration from peripheral organs to lymph nodes plays a key role in initiating immune responses, whether migratory DCs bring antigen in tow to lymph nodes or position themselves to capture antigen that drains into the lymph node. CCR7 prominently controls DC migration into afferent lymphatic vessels and the positioning of DCs within the lymph node. Expression of CCR7 is not sufficient for function, as its function is positively regulated by a variety of other extracellular triggers. At least one of these triggers, synthesis and secretion of PGE₂, is brought on by the activation of p38 MAP kinase. The MAP kinase pathway has been well studied in DCs and exhibits a complex regulatory role in which the activation of different MAP kinase members leads to biologically distinct outcomes that are dependent upon stage of differentiation at the time of activation as well as the duration of signaling. Almost all of our knowledge of how DCs mature and ultimately mobilize to lymph nodes comes from studies in which DC migration is probed in the context of immune activation and priming. A reasonable body of evidence has gathered to suggest that many molecular events important for DC migration in this context do not affect accumulation of DCs in lymph nodes in the steady state, but mediators that interface with the signaling adaptor DAP-12 may play key roles in the steady state. It may thus become possible to devise approaches to modulate DC mobilization in the context of inflammation without affecting the traffic of DCs during more quiescent conditions. Considering the finely tuned regulation of DC maturation, migration, and cytokine production, with the realization that these phenotypes can be mutually exclusive, manipulation of DC migration in the clinic will be a challenging, albeit feasible, task.     

Division of labor between dendritic cell subsets of the lung

Dendritic cells (DCs) are a heterogenous population of antigen-presenting cells, of which conventional DCs and plasmacytoid DCs are the main subsets. Like DC subsets in the central lymphoid organs, DC subsets in the lungs exert specific functions that can be associated with distinct expression of endocytic receptors, cell-surface molecules, and anatomical location within the lung. In recent years, DC populations are increasingly split up into a seemingly endless number of defined sub-populations. We argue that this is not a “stamp-collecting” activity but essential for a deeper understanding of the immune response to pathogens like respiratory viruses or tolerance to harmless antigens. In homeostatic conditions, a fine-tuned balance exists between the various functions of lung DC subsets, which is necessary for maintaining immune homeostasis in the lung. However, infectious or inflammatory conditions can profoundly alter the functions of steady-state DC subsets and recruit inflammatory type DCs to the lung. This might be important for clearing the inflicting pathogenic stimulus, but could at the same time also be involved in causing immune pathology.     

Dendritic cell vaccine design: strategies for eliciting peripheral tolerance as therapy of autoimmune diseases

Dendritic cells (DC), as potent antigen-presenting cells (APC), constitute a complex system of cells that initiate and regulate immune responses that result in two opposite outcomes: immunity or tolerance. The fine regulation of these two distinct functions is not completely understood. After loading with antigen, DC exhibit the properties of both antigen and adjuvant, the functional components of vaccines. For a long time, attention has focused on the exceptional ability of DC as professional APC capable of eliciting T and B cell-mediated responses, and on their potential as immunotherapy in cancer. DC exhibit both heterogeneity and plasticity. On the one hand, distinct DC subsets exhibit distinct functions. On the other hand, DC functions can be altered by the cytokine environment or other factors. There is increasing evidence that DC could be used as a tool to induce peripheral tolerance. Because DC-based immunotherapy in autoimmune diseases depends on tolerogenic DC, discerning markers for tolerogenic DC is of great importance. Immature DC, plasmacytoid DC and interleukin-10-modified DC can mediate immune tolerance by inducing T-cell anergy or T-helper type 2 responses. Several possibilities exist for rational modulation of DC to achieve therapeutic tolerance against autoimmune diseases. The final goal is to create optimal prerequisites to use autologous DC that are prepared from the individual patient with autoimmune disease, to render such DC tolerogenic by exposure in vitro to factors that promote tolerogenicity, and to re-infuse these pretreated DC to the patient in order to treat the ongoing autoimmune disease and prevent its future exacerbation.     

Distinct roles of myeloid and plasmacytoid dendritic cells in systemic lupus erythematosus

Dendritic cells (DCs) constitute a heterogeneous population of professional antigen presenting cells which are the initiators and key regulators for both immunity and tolerance induction. The significance and impact of DC biology in contemporary immunology and medical research is heightened by the award of the 2011 Nobel Prize for Medicine and Physiology to Ralf Steinman for his discovery and subsequent work on the role of DC in adaptive immunity. As a central regulator of immune responses, DCs also play a pivotal role in the pathogenesis of chronic inflammatory autoimmune conditions such as systemic lupus erythematosus (SLE). In this review, we will focus on the respective role of the two major subsets of blood DC, namely myeloid (m)-DC and plasmacytoid (p)-DC, in SLE immunopathogenesis. Accumulating evidence has highlighted pDCs as the culprit for SLE pathogenesis, mainly through type-I interferon production. Latest findings in the field also decipher the mechanisms by which pDCs interact with neutrophils and platelets and contribute to SLE development. The recent surge of interest in studying microRNA regulation in SLE pathogenesis will also be discussed.     

Taking the lymphatic route: dendritic cell migration to draining lymph nodes

In contrast to leukocyte migration through blood vessels, trafficking via lymphatic vessels (LVs) is much less well characterized. An important cell type migrating via this route is antigen-presenting dendritic cells (DCs), which are key for the induction of protective immunity as well as for the maintenance of immunological tolerance. In this review, we will summarize and discuss current knowledge of the cellular and molecular events that control DC migration from the skin towards, into, and within LVs, followed by DC arrival and migration in draining lymph nodes. Finally, we will discuss potential strategies to therapeutically target this migratory step to modulate immune responses.     

Human Dendritic Cell Subsets for Vaccination

TProtective immunity results from the interplay of antigen (Ag)-nonspecific innate immunity and Ag-specific adaptive immunity. The cells and molecules of the innate system employ non-clonal recognition pathways such as lectins and TLRs. B and T lymphocytes of the adaptive immune system employ clonal receptors recognizing Ag or peptides in a highly specific manner. An essential link between innate and adaptive immunity is provided by dendritic cells (DCs). As a component of the innate immunc system, DC organize and transfer information from the outside world to the cells of the adaptive immune system. DC can induce such contrasting states as active immune responsiveness or immunological tolerance. Recent years have brought a wealth of information regarding DC biology and pathophysiology that shows the complexity of this cell system. Thus, presentation of antigen by immature (non-activated) DCs leads to tolerance, whereas mature, antigen-loaded DCs are geared towards the launching of antigen-specific immunity. Furthermore, DCs are composed of multiple subsets with distinct functions at the interface of the innate and adaptive immunity. Our increased understanding of DC pathophysiologywill permit their rational manipulation for therapy such as vaccination to improve immunity.     

Human and murine model cell lines for dendritic cell biology evaluated

Dendritic cells (DCs) are specialized antigen presenting cells that link innate and adaptive immune responses. As key mediators of T cell dependent immunity, DCs are considered primary targets for initiating immune responses in infectious diseases and cancer. Conversely, DCs can also play an important role in the induction of tolerance in organ transplantation, autoimmune disorders and allergy. While DCs have been used in clinical trials worldwide during the past decade, many of the highly specialized cell biological characteristics of DCs remain poorly understood. Small numbers of DCs can be isolated as terminally differentiated, post-mitotic cells form either blood or spleen. Alternatively, DC-precursors, such as monocytes or bone marrow-derived stem cells, can be isolated and differentiated into DCs in vitro. The relative low numbers of cells that can thus be obtained, combined with difficulties manipulating these terminally differentiated primary cells in vitro and in vivo, have seriously hampered studies aimed at exploring the cell biology of DCs. Good model cell lines therefore provide invaluable tools to study DC biology. So far most DC models are myeloid leukemia-derived cell lines that can be differentiated in vitro towards a DC phenotype. Here, we compared the phenotypical and functional characteristics of frequently used mouse and human DC-model cell lines. We conclude that, although none of these cell lines fully recapitulates all cell biological or immunological features of primary DCs, some of these cell lines provide valuable tools to study specific aspects of DC biology.