Role Of Dendritic Cells Subsets Research Articles

Catching Our Breath: Updates on the Role of Dendritic Cell Subsets in Asthma.

Dendritic cells (DCs), as potent antigen presenting cells, are known to play a central role in the pathophysiology of asthma. The understanding of DC biology has evolved over the years to include multiple subsets of DCs with distinct functions in the initiation and maintenance of asthma. Furthermore, asthma is increasingly recognized as a heterogeneous disease with potentially diverse underlying mechanisms. The goal of this review is to summarize the role of DCs and the various subsets therein in the pathophysiology of asthma and highlight some of the crucial animal models shaping the field today. Potential future avenues of investigation to address existing gaps in knowledge are discussed.

The Role of Dendritic Cell Subsets in Recurrent Spontaneous Abortion and the Regulatory Effect of Baicalin on It.

Recurrent spontaneous abortion (RSA) is a relevant complication of pregnancy. Aberrant dendritic cell (DC) activities and differentiation have been identified to be involved in RSA, but the underlying mechanisms remain unclear. Baicalin from Radix Scutellariae possesses a wide range of pharmacological and biological activities. However, the effect of baicalin on DC function in RSA has not been investigated. Here, we analyzed the changes of peripheral and maternal-fetal interface DC subsets and function in patients and mice with RSA, respectively. Then, we further treated RSA mice with baicalin and analyzed the therapeutic effect and underlying mechanism. We found that DCs from the peripheral blood and decidua of RSA patients and the maternal-fetal of RSA mice were all polarized to conventional DCs, whose proportion was positively correlated with the mice embryo absorption rate. Moreover, DCs from RSA patients and mice showed increased expression of HLA-DR/MHC-II, CD80, and CD86 but decreased expression of CD274 and 33D1. Importantly, baicalin could alleviate embryo resorption of RSA mice by reversing conventional DCs to plasmacytoid DCs and functional molecule expression via inhibiting the STAT5-ID2 pathway. Our research further proved that DCs play an important role in the pathogenesis of RSA and baicalin might be used for treating RSA.

Management and Outcomes of Blast Transformed Chronic Myelomonocytic Leukemia.

Despite recent advances in the treatment of de novo acute myeloid leukemia (AML), AML arising from antecedent chronic myelomonocytic leukemia (CMML) continues to have dismal outcomes. While the unique biological drivers of CMML and subsequent leukemic transformation (LT) have been revealed with advances in molecular characterization, this has not yet translated to the bedside. Here, we review these biologic drivers, outcomes with current therapies, and rationale avenues of future investigation specifically in blast phase CMML (CMML-BP). CMML-BP outcomes are studied as an aggregate with more common categories of AML with myelodysplasia-related changes (AML-MRCs) or the even broader category of secondary AML (sAML), which illustrates the crux of the problem. While a modest survival advantage with allogeneic hematopoietic stem cell transplant exists, the difficulty is bridging patients to transplant and managing patients that require an allograft-sparing approach. Limited data suggest that short-lived remissions can be obtained employing CPX-351 or venetoclax-based lower intensity combination therapy. Promising future strategies include repurposing cladribine, exploiting the supportive role of dendritic cell subsets with anti-CD123 therapies, MCL-1 inhibition, dual MEK/PLK1 inhibition, FLT3 inhibition in RAS-mutated and CBL-mutated subsets, and immune therapies targeting novel immune checkpoint molecules such as the leukocyte immunoglobulin-like receptor B4 (LILRB4), an immune-modulatory transmembrane protein restrictively expressed on monocytic cells. The successful management of an entity as unique as CMML-BP will require a cooperative, concerted effort to design and conduct clinical trials dedicated to this rare form of sAML.

Functional Role of Dendritic Cell Subsets in Cancer Progression and Clinical Implications.

Dendritic cells (DCs) constitute a complex network of cell subsets with common functions but also with many divergent aspects. All dendritic cell subsets share the ability to prime T cell response and to undergo a complex trafficking program related to their stage of maturation and function. For these reasons, dendritic cells are implicated in a large variety of both protective and detrimental immune responses, including a crucial role in promoting anti-tumor responses. Although cDC1s are the most potent subset in tumor antigen cross-presentation, they are not sufficient to induce full-strength anti-tumor cytotoxic T cell response and need close interaction and cooperativity with the other dendritic cell subsets, namely cDC2s and pDCs. This review will take into consideration different aspects of DC biology, including the functional role of dendritic cell subsets in both fostering and suppressing tumor growth, the mechanisms underlying their recruitment into the tumor microenvironment, as well as the prognostic value and the potentiality of dendritic cell therapeutic targeting. Understanding the specificity of dendritic cell subsets will allow to gain insights on role of these cells in pathological conditions and to design new selective promising therapeutic approaches.

Listeria Monocytogenes: A Model Pathogen Continues to Refine Our Knowledge of the CD8 T Cell Response.

Listeria monocytogenes (Lm) infection induces robust CD8 T cell responses, which play a critical role in resolving Lm during primary infection and provide protective immunity to re-infections. Comprehensive studies have been conducted to delineate the CD8 T cell response after Lm infection. In this review, the generation of the CD8 T cell response to Lm infection will be discussed. The role of dendritic cell subsets in acquiring and presenting Lm antigens to CD8 T cells and the events that occur during T cell priming and activation will be addressed. CD8 T cell expansion, differentiation and contraction as well as the signals that regulate these processes during Lm infection will be explored. Finally, the formation of memory CD8 T cell subsets in the circulation and in the intestine will be analyzed. Recently, the study of CD8 T cell responses to Lm infection has begun to shift focus from the intravenous infection model to a natural oral infection model as the humanized mouse and murinized Lm have become readily available. Recent findings in the generation of CD8 T cell responses to oral infection using murinized Lm will be explored throughout the review. Finally, CD8 T cell-mediated protective immunity against Lm infection and the use of Lm as a vaccine vector for cancer immunotherapy will be highlighted. Overall, this review will provide detailed knowledge on the biology of CD8 T cell responses after Lm infection that may shed light on improving rational vaccine design.

Opposing Roles of Dendritic Cell Subsets in Experimental GN.

Dendritic cells (DCs) are thought to form a dendritic network across barrier surfaces and throughout organs, including the kidney, to perform an important sentinel function. However, previous studies of DC function used markers, such as CD11c or CX3CR1, that are not unique to DCs. Here, we evaluated the role of DCs in renal inflammation using a CD11c reporter mouse line and two mouse lines with DC-specific reporters, Zbtb46-GFP and Snx22-GFP. Multiphoton microscopy of kidney sections confirmed that most of the dendritically shaped CD11c+ cells forming a network throughout the renal interstitium expressed macrophage-specific markers. In contrast, DCs marked by Zbtb46-GFP or Snx22-GFP were less abundant, concentrated around blood vessels, and round in shape. We confirmed this pattern of localization using imaging mass cytometry. Motility measurements showed that resident macrophages were sessile, whereas DCs were motile before and after inflammation. Although uninflamed glomeruli rarely contained DCs, injury with nephrotoxic antibodies resulted in accumulation of ZBTB46 + cells in the periglomerular region. ZBTB46 identifies all classic DCs, which can be categorized into two functional subsets that express either CD103 or CD11b. Depletion of ZBTB46 + cells attenuated the antibody-induced kidney injury, whereas deficiency of the CD103+ subset accelerated injury through a mechanism that involved increased neutrophil infiltration. RNA sequencing 7 days after nephrotoxic antibody injection showed that CD11b+ DCs expressed the neutrophil-attracting cytokine CXCL2, whereas CD103+ DCs expressed high levels of several anti-inflammatory genes. These results provide new insights into the distinct functions of the two major DC subsets in glomerular inflammation.

The role of dendritic cells in male reproductive tract.

Dendritic cells (DCs) are the most potent professional antigen-presenting cells. The central role of various DC subsets as bridges between innate and adaptive immunity has become more and more evident. However, the role of DC subsets in male reproductive tract remains largely unexplored, in particular distinct DC subsets (including myeloid and plasmacytoid DCs), their maturation stage, and tissue distribution, as well as state of health or disease. Furthermore, infection and inflammation of male genital tract are thought to be a primary etiological factor of male infertility. This review sheds some light on this complex and rapidly growing field. It summarized the recent findings and deals with the characterization and role of DCs in male reproductive tract, that is, testis, epididymis, prostate, seminal vesicle, semen, and foreskin, which might help to understand the immunopathological mechanisms of male infertility and design effective vaccines for male reproductive health.

78. Distinct Roles of Dendritic Cell Subsets in Innate Immune Sensing and Cross-Presentation of AAV Capsid In Vivo

Immune responses to AAV vectors currently represent one of the greatest hurdles facing successful gene therapy. Adeno-associated virus (AAV) vectors have been investigated in clinical trials for treatment of hemophilia B. However, in these trials, it was shown that transduced hepatocytes are eliminated by capsid specific CD8+ T cells, resulting in a loss of transgene expression and therapeutic efficacy. AAV capsid proteins are not endogenously expressed and therefore must be loaded on MHC class I via cross-presentation, a poorly understood mechanism relatively unique to conventional dendritic cells (cDCs). Previous work in our lab has shown that selective depletion of cDCs using CD11c-DTR mice ablates the anti-capsid CD8+ T cell response, and that innate sensing of the AAV genome is mediated through TLR9-sensing of the DNA genome and downstream signaling through its adaptor protein, MyD88. A second subset of dendritic cells, called plasmacytoid DCs (pDCs), highly express TLR9 and secrete large amounts of type I interferon following activation from a viral stimulus. Herein, we investigated the respective roles of cDCs and pDCs in the cross-presentation of capsid antigen. To measure capsid-specific T cell responses, we have created a modified AAV2 capsid that contains the peptide sequence SIINFEKL (AAV2-SIINFEKL), which is the CD8+ immunodominant epitope of the model antigen ovalbumin in C57BL/6 mice. With this vector, capsid-specific CD8+ T cells can be identified using H2-Kb-SIINFEKL tetramer. We first confirmed the requirement of cDCs in capsid cross-presentation by measuring the proliferation of adoptively transferred T cells from TCR transgenic OT-1 mice, which produce CD8+ restricted, OVA-specific T cells, into cDC-depleted CD11c-DTR mice (n=4) that received AAV2-SIINFEKL. After 7 days, OT-I T cell proliferation was ~3% in the absence of cDCs compared to ~27% in the presence of cDCs. Strikingly, we found that the specific depletion of pDCs in BDCA2-DTR mice (n=4) that received AAV2-SIINFEKL also resulted in suppressed capsid CD8+ T cell formation, suggesting discrete yet essential roles for both pDCs and cDCs in the initiation of a cytotoxic T lymphocyte (CTL) response directed against AAV capsid antigen. To dissect the specific roles of cDCs and pDCs, we first investigated the requirement for MyD88 in cDCs by generating a transgenic mouse expressing Cre-recombinase under the control of the CD11c promoter with the MyD88 gene flanked by LoxP sites, specifically ablating MyD88 expression in cDCs (DC-MyD88−/− mice). We observed no significant difference in tetramer positive CD8+ T cells between DC-MyD88−/− mice (n=4) and WT mice, indicating that cDC-intrinsic MyD88 signaling is not required for the formation of anti-capsid CTL responses. Importantly, pDCs retained MyD88 expression in this model. To precisely define the role of TLR9 in these DC subsets, we adoptively transferred either WT pDCs (n=9) or WT cDCs (n=9) into TLR9−/− mice followed by injection of AAV2-SIINFEKL. Adoptive transfer of WT pDCs but not of WT cDCs restored induction of tetramer positive CD8+ T cells in the TLR9−/− mice. Therefore, we propose a 2-step model for anti-capsid CD8+ T cell responses to AAV vectors in which innate recognition of the genome occurs in pDCs via the TLR9-MyD88 pathway, promoting the cross-presentation of capsid antigen by cDCs. These results establish both DC subsets as critically important in the initiation of anti-capsid CD8+ T cell responses to AAV vectors and unveil potential targets to mitigate the deleterious effects of the immune response to AAV gene therapy.

Editorial: "Cancer Immunotherapy: Lights and Shadows".

Editorial: "Cancer Immunotherapy: Lights and Shadows".

The Role of Dendritic Cell Subsets and Innate Immunity in the Pathogenesis of Type 1 Diabetes and Other Autoimmune Diseases.

Dendritic cells (DCs) are key antigen-presenting cells that have an important role in autoimmune pathogenesis. DCs control both steady-state T cell tolerance and activation of pathogenic responses. The balance between these two outcomes depends on several factors, including genetic susceptibility, environmental signals that stimulate varied innate responses, and which DC subset is presenting antigen. Although the specific DC phenotype can diverge depending on the tissue location and context, there are four main subsets identified in both mouse and human: conventional cDC1 and cDC2, plasmacytoid DCs, and monocyte-derived DCs. In this review, we will discuss the role of these subsets in autoimmune pathogenesis and regulation, as well as the genetic and environmental signals that influence their function. Specific topics to be addressed include impact of susceptibility loci on DC subsets, alterations in DC subset development, the role of infection- and host-derived innate inflammatory signals, and the role of the intestinal microbiota on DC phenotype. The effects of these various signals on disease progression and the relative effects of DC subset composition and maturation level of DCs will be examined. These areas will be explored using examples from several autoimmune diseases but will focus mainly on type 1 diabetes.

Dendritic Cell-Based Vaccination in Cancer: Therapeutic Implications Emerging from Murine Models

Dendritic cells (DCs) play a pivotal role in the orchestration of immune responses, and are thus key targets in cancer vaccine design. Since the 2010 FDA approval of the first cancer DC-based vaccine (Sipuleucel-T), there has been a surge of interest in exploiting these cells as a therapeutic option for the treatment of tumors of diverse origin. In spite of the encouraging results obtained in the clinic, many elements of DC-based vaccination strategies need to be optimized. In this context, the use of experimental cancer models can help direct efforts toward an effective vaccine design. This paper reviews recent findings in murine models regarding the antitumoral mechanisms of DC-based vaccination, covering issues related to antigen sources, the use of adjuvants and maturing agents, and the role of DC subsets and their interaction in the initiation of antitumoral immune responses. The summary of such diverse aspects will highlight advantages and drawbacks in the use of murine models, and contribute to the design of successful DC-based translational approaches for cancer treatment.

The pathophysiological role of dendritic cell subsets in psoriasis

Psoriasis is a chronic inflammatory disorder characterized by an erythematous scaly plaque of the skin and is occasionally accompanied by systemic complications. In the psoriatic lesions, an increased number of cytokine-producing dendritic cells and activated T cells are observed, which indicate that psoriasis is a prototype of an immune-mediated dermatosis. During the last decade, emerging studies demonstrate novel roles for the dendritic cell subsets in the process of disease initiation and maintenance of psoriasis. In addition, recently discovered anti-psoriatic therapies, which specifically target inflammatory cytokines produced by lesional dendritic cells, bring much better clinical improvement compared to conventional treatments. These new therapies implicate the crucial importance of dendritic cells in psoriasis pathogenesis. This review will summarize and discuss the dendritic cell subsets of the human skin and their pathophysiological involvement in psoriasis based on mouse- and patient-oriented studies. [BMB Reports 2014; 47(2): 60-68]

The Role of Dendritic Cells in Tissue-Specific Autoimmunity

In this review, we explore the role of dendritic cell subsets in the development of tissue-specific autoimmune diseases. From the increasing list of dendritic cell subclasses, it is becoming clear that we are only at the beginning of understanding the role of these antigen presenting cells in mediating autoimmunity. Emerging research areas for the study of dendritic cell involvement in the onset and inhibition of tissue-specific autoimmunity are presented. Further, we compare tissue specific to systemic autoimmunity to demonstrate how development of dendritic cell-based therapies may be broadly applicable to both classes of autoimmunity. Continued development of these research areas will lead us closer to clinical assessment of novel immunosuppressive therapy for the reversal and prevention of tissue-specific autoimmunity. Through description of dendritic cell functions in the modulation of tissue-specific autoimmunity, we hope to stimulate a greater appreciation and understanding of the role dendritic cells play in the development and treatment of autoimmunity.

The role of dendritic cells in the pathogenesis of cigarette smoke-induced emphysema in mice

Chronic Obstructive Pulmonary Disease (COPD) is an important lung and airway disease which affects the lives of around 200 million people worldwide. The pathological hallmark of COPD is emphysema and bronchiolitis and is based on the inflammatory response of the innate and adaptive immune system to the inhalation of toxic particles and gases. The inflamed airways of COPD patients contain several inflammatory cells including neutrophils, macrophages, T lymphocytes, and dendritic cells (DC). The potential role of DCs as mediators of inflammation in the airways of smokers and COPD patients is poorly understood. The current study investigated the role of DC subsets in an animal model of cigarette smoke-induced lung emphysema through the expansion or depletion of DC subsets. Expansion of both myeloid DC (mDC) and plasmacytoid DC (pDC) by Flt3L treatment induced a decline in macrophage numbers and increased the levels of fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) in the bronchoalveolar lavage (BAL) fluid of smoke-exposed animals. The increase in the mean linear intercept (Lm) following Flt3L treatment was decreased by pDC depletion. In conclusion, pharmacological modulation of DC subsets may have an effect on the development of airway responses and emphysema as indicated by the decline in macrophage numbers and the increase in FGF and VEGF levels in the bronchoalveolar lavage fluid. Moreover, the depletion of pDCs decreased the Lm which might suggest a role for pDC in the pathogenesis of lung emphysema.

Dendritic Cell Subsets in Type 1 Diabetes: Friend or Foe?

Type 1 diabetes (T1D) is a T cell mediated autoimmune disease characterized by immune mediated destruction of the insulin-producing β cells in the islets of Langerhans. Dendritic cells (DC) have been implicated in the pathogenesis of T1D and are also used as immunotherapeutic agents. Plasmacytoid (p)DC have been shown to have both protective and pathogenic effects and a newly described merocytic DC population has been shown to break tolerance in the mouse model of T1D, the non-obese diabetic (NOD) mouse. We have used DC populations to prevent the onset of T1D in NOD mice and clinical trials of DC therapy in T1D diabetes have been initiated. In this review we will critically examine the recent published literature on the role of DC subsets in the induction and regulation of the autoimmune response in T1D.

Extrafollicular B cell activation by marginal zone dendritic cells drives T cell–dependent antibody responses

Dendritic cells (DCs) are best known for their ability to activate naive T cells, and emerging evidence suggests that distinct DC subsets induce specialized T cell responses. However, little is known concerning the role of DC subsets in the initiation of B cell responses. We report that antigen (Ag) delivery to DC-inhibitory receptor 2 (DCIR2) found on marginal zone (MZ)-associated CD8α(-) DCs in mice leads to robust class-switched antibody (Ab) responses to a T cell-dependent (TD) Ag. DCIR2(+) DCs induced rapid up-regulation of multiple B cell activation markers and changes in chemokine receptor expression, resulting in accumulation of Ag-specific B cells within extrafollicular splenic bridging channels as early as 24 h after immunization. Ag-specific B cells primed by DCIR2(+) DCs were remarkably efficient at driving naive CD4 T cell proliferation, yet DCIR2-induced responses failed to form germinal centers or undergo affinity maturation of serum Ab unless toll-like receptor (TLR) 7 or TLR9 agonists were included at the time of immunization. These results demonstrate DCIR2(+) DCs have a unique capacity to initiate extrafollicular B cell responses to TD Ag, and thus define a novel division of labor among splenic DC subsets for B cell activation during humoral immune responses.

News from dendritic cells in atopic dermatitis

Dendritic cells are essential for the generation of innate and adaptive immune responses, which makes them stay on center stage when studying the immuno pathogenesis of atopic dermatitis. This review will discuss recent findings on the role of dendritic cells subsets in atopic dermatitis and will report novel findings on how the microenvironment conditions dendritic cells to fuel atopic dermatitis. Several microenvironmental factors characteristic for atopic dermatitis and with direct relevance for the disease have been defined. We now increasingly understand how thymic stromal lymphopoietin and histamine contribute to the disease by modulating the function of dendritic cells. We have learned much about the pathogenesis of atopic dermatitis by the studies on inflammatory dendritic epidermal cells. However, the current analysis on the functional and phenotypic heterogeneity of dendritic cells in eczematous skin lesions may lead to the definition of additional dendritic cell types relevant in the pathogenesis of atopic dermatitis. In this respect, it appears interesting to further discuss the parallels and differences in atopic dermatitis and psoriasis. Understanding the heterogeneity of dendritic cells and their functional alteration by local factors in the inflamed skin will provide essential clues to the immunopathogenesis of atopic dermatitis.

Leishmaniasis, contact hypersensitivity and graft‐versus‐host disease: understanding the role of dendritic cell subsets in balancing skin immunity and tolerance

Dendritic cells (DC) are key elements of the immune system. In peripheral tissues, they function as sentinels taking up and processing antigens. After migration to the draining lymph nodes, the DC either present antigenic peptides by themselves or transfer them to lymph node-resident DC. The skin is the primary interface between the body and the environment and host's various DC subsets, including dermal DC (dDC) and Langerhans cells (LC). Because of their anatomical position in the epidermis, LC are believed to be responsible for induction of adaptive cutaneous immune responses. The functions of LC and dDC in the skin immune system in vivo are manifold, and it is still discussed controversially whether the differentiation of T-cell subtypes (e.g. effector T cells and regulatory T cells) may be initiated by distinct DC subtypes. As skin DC are able to promote or downmodulate immune responses, we chose different skin diseases (cutaneous leishmaniasis, contact hypersensitivity, UV radiation-induced suppression, and graft-versus-host disease) to describe the biological interactions between different DC subtypes and T cells that lead to the development of efficient or unwanted immune responses. A detailed knowledge about the immune modulatory capacity of different cutaneous DC subsets might be helpful to specifically target these cells through the skin during therapeutic interventions.

W1805 The Role of Dendritic Cell Subsets in 2,4,6-Trinitrobenzene Sulfonic Acid-Induced Ileitis

W1805 The Role of Dendritic Cell Subsets in 2,4,6-Trinitrobenzene Sulfonic Acid-Induced Ileitis

Dendritic cell subsets in primary and secondary T cell responses at body surfaces

We examine the role of dendritic cells subsets in immunity to peripheral infections, with emphasis on the differences in the regulation of primary and secondary T cell responses to viruses. Our major focus is on new developments in the understanding of immunity to infections of the skin and lung, which are crucial entry points for a variety of infectious pathogens. Initially we describe a diverse network of dendritic cell subsets, but then we argue for a more generalized model of reduced complexity.