Regulation Of Dendritic Cell Function Research Articles

Regulation of Dendritic Cell Function by Surfactant Protein D

RATIONALE: Surfactant protein-D (SP-D) plays an important protective role and may modulate dendritic cells (DC) in the lung. How SP-D affects pulmonary DC function is unclear.METHODS: Expression of the DC-associated chemokines and their receptors Ccl17 (TARC), 19 and 21, Ccr4 and 7 was analyzed by real-time PCR, ELISA and flow cytometry in lungs and thoracic lymph nodes of conditional SP-D expressor and SP-D-/- mice sensitized and challenged with the allergen Aspergillus fumigatus (Af). The direct effect of SP-D on DC maturation from bone marrow derived progenitor cells was analyzed in vitro by immunocytochemistry and flow cytometry.RESULTS: SP-D-/- mice showed accumulation of lymphocytes in the airway submucosal tissue and had a nearly 10-fold higher expression of Ccl17 and its receptor, Ccr4, than SP-D+/+ mice, suggesting local activation of Th2 cells. Indeed, expression of Ccr7, the receptor responsible for facilitating migration of lung DC to the thoracic lymph nodes, was significantly reduced in the lung tissue of SP-D-/- mice following intranasal challenge of sensitized mice with Af. Concurrent inhalation of a fluorescein label (CFSE) revealed that allergen uptake did not induce retrograde migration of DC in the lung of SP-D-/- mice: The number of CD11c+/CFSE+ cells recovered from the thoracic lymph nodes of these mice was significantly reduced in comparison with SP-D+/+ mice.CONCLUSIONS: Since SP-D markedly inhibited expression of CD86 and MHC-II in vitro, we conclude that presence of this innate immune molecule is essential for compartmentalization of the immune response to the lymph nodes. RATIONALE: Surfactant protein-D (SP-D) plays an important protective role and may modulate dendritic cells (DC) in the lung. How SP-D affects pulmonary DC function is unclear. METHODS: Expression of the DC-associated chemokines and their receptors Ccl17 (TARC), 19 and 21, Ccr4 and 7 was analyzed by real-time PCR, ELISA and flow cytometry in lungs and thoracic lymph nodes of conditional SP-D expressor and SP-D-/- mice sensitized and challenged with the allergen Aspergillus fumigatus (Af). The direct effect of SP-D on DC maturation from bone marrow derived progenitor cells was analyzed in vitro by immunocytochemistry and flow cytometry. RESULTS: SP-D-/- mice showed accumulation of lymphocytes in the airway submucosal tissue and had a nearly 10-fold higher expression of Ccl17 and its receptor, Ccr4, than SP-D+/+ mice, suggesting local activation of Th2 cells. Indeed, expression of Ccr7, the receptor responsible for facilitating migration of lung DC to the thoracic lymph nodes, was significantly reduced in the lung tissue of SP-D-/- mice following intranasal challenge of sensitized mice with Af. Concurrent inhalation of a fluorescein label (CFSE) revealed that allergen uptake did not induce retrograde migration of DC in the lung of SP-D-/- mice: The number of CD11c+/CFSE+ cells recovered from the thoracic lymph nodes of these mice was significantly reduced in comparison with SP-D+/+ mice. CONCLUSIONS: Since SP-D markedly inhibited expression of CD86 and MHC-II in vitro, we conclude that presence of this innate immune molecule is essential for compartmentalization of the immune response to the lymph nodes.

Shaping immune responses through the activation of dendritic cells’ P2 receptors

Dendritic cells (DCs) activate and shape the adaptive immune response by capturing antigens, migrating to peripheral lymphoid organs where naïve T cells reside, expressing high levels of MHC and costimulatory molecules and secreting cytokines and chemokines. DCs are endowed with a high degree of functional plasticity and their functions are tightly regulated. Besides initiating adaptive immune responses, DCs play a key role in maintaining peripheral tolerance toward self-antigens. On the basis of the information gathered from the tissue where they reside, DCs adjust their functional activity to ensure that protective immunity is favoured while unwanted or exaggerated immune responses are prevented. A wide variety of signals from neighbouring cells affecting DC functional activity have been described. Here we will discuss the complex role of extracellular nucleotides in the regulation of DC function and the role of P2 receptors as possible tools to manipulate immune responses.

Comparative Roles of IL-4, IL-13, and IL-4Rα in Dendritic Cell Maturation and CD4+ Th2 Cell Function

IL-4 and IL-13 play key roles in Th2 immunity and asthma pathogenesis. Although the function of these cytokines is partially linked through their shared use of IL-4Ralpha for signaling, the interplay between these cytokines in the development of memory Th2 responses is not well delineated. In this investigation, we show that both IL-4 and IL-13 influence the maturation of dendritic cells (DC) in the lung and their ability to regulate secretion of IFN-gamma and Th2 cytokines by memory CD4(+) T cells. Cocultures of wild-type T cells with pulmonary DC from allergic, cytokine-deficient mice demonstrated that IL-4 enhanced the capacity of DC to stimulate T cell secretion of Th2 cytokines, whereas IL-13 enhanced the capacity of DC to suppress T cell secretion of IFN-gamma. Because IL-4Ralpha is critical for IL-4 and IL-13 signaling, we also determined how variants of IL-4Ralpha influenced immune cell function. T cells derived from allergic mice expressing a high-affinity IL-4Ralpha variant produced higher levels of IL-5 and IL-13 compared with T cells derived from allergic mice expressing a low-affinity IL-4Ralpha variant. Although DC expressing different IL-4Ralpha variants did not differ in their capacity to influence Th2 cytokine production, they varied in their capacity to inhibit IFN-gamma production by T cells. Thus, IL-4 and IL-13 differentially regulate DC function and the way these cells regulate T cells. The affinity of IL-4Ralpha also appears to be a determinant in the balance between Th2 and IFN-gamma responses and thus the severity of allergic disease.

Regulation of Dendritic Cell Function and T Cell Priming by the Fatty Acid-Binding Protein aP2

The fatty acid-binding protein (FABP) family consists of a number of conserved cytoplasmic proteins with roles in intracellular lipid transport, storage, and metabolism. Examination of a comprehensive leukocyte gene expression database revealed strong expression of the adipocyte FABP aP2 in human monocyte-derived dendritic cells (DCs). We isolated bone marrow-derived DC from aP2-deficient mice, and showed that expression of DC cytokines including IL-12 and TNF was significantly impaired in these cells. Degradation of IkappaBalpha was also impaired in aP2-deficient DCs, indicative of reduced signaling through the IkappaB kinase-NF-kappaB pathway. The cytokine defect was selective because there was no effect on Ag uptake or expression of MHC class II, CD40, CD80, or CD86. In an MLR, aP2-deficient DCs stimulated markedly lower T cell proliferation and cytokine production than did wild-type DCs. Moreover, aP2-deficient mice immunized with keyhole limpet hemocyanin/CFA showed reduced production of IFN-gamma by restimulated draining lymph node cells, suggesting a similar defect in DC function in vivo. Similarly, infection of aP2-deficient mice with the natural mouse pathogen ectromelia virus resulted in substantially lower production of IFN-gamma by CD8+ T cells. Thus, FABP aP2 plays an important role in DC function and T cell priming, and provides an additional link between metabolic processes and the regulation of immune responses.

Regulation of Dendritic Cell Function by Histone Deacetylase Inhibitors.

Histone deacetylases (HDACs) modulate gene transcription and chromatin assembly by modifying histones at the post-transcriptional level. HDAC inhibitors have promising antitumor activity and are presently explored in clinical studies for malignancies of different histology. Preliminary evidence in animal models of immune disorders also suggests immunosuppressive properties for these small molecules, although the underlying mechanisms remain at present poorly understood. Here, we show that two HDAC inhibitors of clinical use, sodium valproate and MS-275, profoundly affect cytokine-induced differentiation of human monocytes to dendritic cells (DCs), and impair DC phenotypic maturation in response to the Toll-like receptor (TLR) ligand polyinosinic:polycytidylic acid (poly I:C) characterized by a reduced expression of HLA- and costimulatory molecules. HDAC inhibitors reduce cytokine secretion important for T-cell activation like IL-12 and immunostimulatory capacity in DCs and inhibit DC migratory capacity toward the chemoattractant CCL19/MIP-3β. The observed defects in DC function upon exposure to HDAC inhibitors were not due to an increased rate of apoptosis or production of IL-10. We finally investigated the effects of HDAC inhibition on intracellular signalling pathways that play a key role in controlling DC differentiation and function. HDAC inhibitors have been reported to cause a downregulation of the hematopoietic transcription factor PU.1, which contributes to the development of thymic and myeloid dendritic cells and of Langerhans cells in the mouse. We evaluated herein whether PU.1 expression was affected by VPA in monocyte-derived DCs, however, no significant reduction in protein levels could be detected. Therefore, our data rule out PU.1 shortening as a mechanism responsible for the functional defects observed in DCs that were exposed to HDAC inhibitors. Similarly, no significant effect of HDAC inhibitors was detected on Bcl-6, another known target of HDAC inhibitors that, besides its role in lymphomas, has also been linked to the regulation of cytokine and chemokine release in macrophages. In contrast, addition of VPA blocked RelB nuclear relocalization in response to poly I:C in a concentration-dependent manner. Interestingly, IRF-3 and IRF-8, which have been involved in DC differentiation, IL-12 production and DC migration, were also affected by HDAC inhibitors, since their nuclear levels were reduced by VPA in unstimulated as well as in poly I:C-activated DCs. On the other hand, IRAK-1 downregulation in response to poly I:C was not affected by VPA, suggesting that the effects of HDAC inhibition on RelB, IRF-3 and IRF-8 are probably mediated downstream of MyD88 and IRAK-1.In conclusion, HDAC inhibitors exhibit strong immunomodulatory properties on human DCs. Our results support the evaluation of HDAC inhibitors in inflammatory and autoimmune disorders.

PPARγ, a Lipid‐Activated Transcription Factor as a Regulator of Dendritic Cell Function

In recent years it became apparent that PPARgamma, besides being a key component of adipose tissue development and a target of insulin-sensitizing drugs, also has a role in immune cell differentiation and function. This receptor has been identified by us and others as a conductor of lipid handling in macrophages, and has roles also in inflammation control. Here we review recent advances on the role of this nuclear receptor in another key cell type of myeloid origin, dendritic cells (DCs). DCs are professional antigen-presenting cells having essential roles in antigen-uptake processing and presentation and in initiation of various forms of immune responses. It appears that PPARgamma is expressed and is active in myeloid DCs and likely to be a regulator of DC function by altering antigen uptake, maturation, activation, migration, cytokine production, and lipid antigen presentation. Thus PPARgamma is at the crossroads of lipid metabolism and innate immune response, and by studying its functions one has a unique opportunity to discern how these two seemingly distant fields (lipid metabolism and immune response) are interrelated. It is also possible that this receptor is a relevant target for pharmacological intervention in immune diseases such as chronic inflammation and autoimmune conditions.

Regulation of Dendritic Cell Differentiation by Vasoactive Intestinal Peptide

Dendritic cells (DCs) are the most potent antigen-presenting cells (APCs) involved in the defense of the body and in the maintenance of the immune tolerance. The regulation of their maturation, migration, and expression of stimulatory and costimulatory molecules has major consequences on the immune response. The endogenous factors that regulate DC function are poorly known. Vasoactive intestinal peptide (VIP) is a neuropeptide with potent anti-inflammatory actions. This anti-inflammatory profile is maintained partially through effects on DC differentiation/function. Thus, VIP has differential effects on DCs, depending on the differentiation and stimulatory states. Immature DCs treated with VIP exhibit increased CD86 expression and induce CD4(+) T cell proliferation. In addition, the CD4(+) T cells activated in vitro or in vivo by VIP-treated iDCs exhibit a Th2 phenotype. In contrast, VIP reduces both CD86 and CD80 expression on lipopolysaccharide (LPS)-stimulated DCs, and inhibits the capacity of DCs to induce in vitro or in vivo T cell proliferation. However, addition of VIP in the early states of DC differentiation results in the generation of DCs that cannot mature following inflammatory stimuli that exhibit a tolerogenic phenotype, characterized by low expression of costimulatory molecules (CD40, CD80, and CD86), low production of proinflammatory cytokines, increased production of IL-10, and capacity to induce regulatory T cells with suppressive actions. The effect of VIP on the DC-Treg axis represents an additional mechanism for their general anti-inflammatory role, particularly relevant in autoimmunity and transplantation.

CD4 T Cell-Induced, Bid-Dependent Apoptosis of Cutaneous Dendritic Cells Regulates T Cell Expansion and Immune Responses

The fate of dendritic cells (DCs) after Ag presentation may be DC subset-specific and controlled by many factors. The role of activation-induced apoptosis in regulating DC function is not clear. We investigated the fate of cutaneous DCs (cDCs), specifically Langerhans cells (LCs), and observed that they undergo apoptosis after successful Ag presentation to CD4 T cells. Caspase-specific inhibitors revealed that LC lines use a type II apoptosis pathway in response to CD4 T cells. In support of this, BH3-interacting domain (Bid) protein was present at high levels and specifically cleaved in the presence of Ag-specific T cells. Significant resistance to apoptosis by OT-2 CD4 cells was also observed for Bid knockout (KO) LCs in vitro. To test whether Bid was required to regulate LC function in vivo, we measured contact sensitization and topical immunization responses in Bid KO mice and observed markedly enhanced ear swelling and proliferation responses compared with wild-type mice. Furthermore, when Ag-pulsed Bid KO migratory cDCs were inoculated into wild-type recipients, an increase in both the rate and percentage of expanded OT-2 T cells expressing IFN-gamma was observed. Thus, enhanced Ag presentation function was intrinsic to Bid KO cDCs. Therefore, Bid is an important regulator of LC viability and Ag presentation function.

Shaping immune responses through the activation of dendritic cells–P2 receptors

Dendritic cells (DCs) activate and shape the adaptive immune response by capturing antigens, migrating to peripheral lymphoid organs where naïve T cells reside, expressing high levels of MHC and costimulatory molecules and secreting cytokines and chemokines. DCs are endowed with a high degree of functional plasticity and their functions are tightly regulated. Besides initiating adaptive immune responses, DCs play a key role in maintaining peripheral tolerance toward self-antigens. On the basis of the information gathered from the tissue where they reside, DCs adjust their functional activity to ensure that protective immunity is favoured while unwanted or exaggerated immune responses are prevented. A wide variety of signals from neighbouring cells affecting DC functional activity have been described. Here we will discuss the complex role of extracellular nucleotides in the regulation of DC function and the role of P2 receptors as possible tools to manipulate immune responses.

Interleukin-10 and Th2 Cytokines Differentially Regulate Osteopontin Expression in Human Monocytes and Dendritic Cells

Osteopontin (OPN) is a pleiotrophic phosphoprotein involved in homeostatic and pathophysiologic responses. It is known to be a chemotactic cytokine for dendritic cells (DCs), a critical cell type in both innate and adaptive immune responses. We report herein a contrasting role of interleukin-10 (IL-10) and Th2 cytokines in the regulation of OPN expression in human monocytes and monocyte-derived DCs (Mo-DCs). Our results showed first that the expression of OPN in monocytes and Mo-DCs was induced in a time-dependent and dose-dependent manner by IL-10 but was inhibited by IL-4 or IL-13. Further, the basal level of OPN expression was also inhibited by IL-4. This inhibitory effect of IL-4 was associated with a faster decay of OPN transcripts and a decreased proximal promoter activity of OPN in IL-4-treated cells. These results demonstrate a novel role of IL-10 and Th2 cytokines in the regulation of DC function through their contrasting regulatory activities on the expression of OPN.

Modification of TLR‐induced activation of human dendritic cells by type I IFN: synergistic interaction with TLR4 but not TLR3 agonists

Upon detection of direct and indirect signs of infection, dendritic cells (DC) undergo functional changes that modify their ability to elicit immune responses. Type I interferon (IFN-alpha/beta), which includes a large family of closely related infection-inducible cytokines, represents one indirect signal that can act as a DC stimulus. We have investigated the ability of IFN-alpha/beta subtypes to affect DC function and to influence DC responses to Toll-like receptor (TLR) agonists (i.e., direct infection-associated signals). Subtle differences were observed among 15 subtypes of IFN-alpha/beta in the ability to stimulate expression of maturation markers and chemokines by human monocyte-derived DC, with IFN-omega being the most unique in its effects. Pre-treatment with IFN-alpha/beta did not alter the ability of DC to mature in response to subsequent contact with TLR agonists, but did modulate their secretion of chemokines. Conversely, IFN-alpha/beta was shown to act synergistically with TLR4 but not TLR3 agonists for the induction of maturation and chemokine production when DC were exposed to IFN-alpha/beta and TLR ligands simultaneously. Taken together, these results indicate a complex role for IFN-alpha/beta in regulating DC function during the course an infection, which varies according to IFN-alpha/beta subtype and the timing of exposure to other stimuli.

Expression, purification, and refolding of the myeloid inhibitory receptor leukocyte immunoglobulin-like receptor-5 for structural and ligand identification studies

The leukocyte immunoglobulin-like receptors (LIRs, also known as ILTs, CD85, and LILRs) comprise a family of related immunoregulatory receptors encoded within the leukocyte receptor cluster (LRC) on human chromosome 19. LIRs are transmembrane proteins containing either two or four extracellular immunoglobulin domains, and most family members are expressed predominantly on myeloid cell lineages. Although the inhibitory receptors LIR-1 and LIR-2 are known to bind to a broad range of class I MHC molecules and are thought to play important roles in immune regulation, the majority of LIRs are currently of unknown structure and their ligands remain unidentified. In this study, we describe recombinant production and characterisation of the extracellular portion of LIR-5 (ILT3), a poorly understood inhibitory receptor that transduces tolerising signals to dendritic cells. The two extracellular immunoglobulin domains of LIR-5 were expressed in Escherichia coli to a high level and were found to accumulate in inclusion bodies. Inclusion bodies were purified, solubilised, and receptor then renatured by dilution refolding, with acceptable yields. Size exclusion chromatography and SDS–PAGE analyses confirmed the extracellular portion behaved as a monomer in solution, and purified protein was antibody-reactive. LIR-5 is representative of a subset of LIR receptors that on the basis of structural and sequence comparisons with LIR-1 seem unlikely to bind class I MHC molecules. Successful prokaryotic generation of correctly folded LIR-5 in high levels has implications for production of other LRC receptors and should greatly facilitate attempts to define the structure and ligands of this important regulator of dendritic cell function.

Cellules immunocompétentes

The skin provides a complex microenvironment where several cell populations actively participate in the initiation and regulation of inflammatory and immune responses. Cutaneous dendritic cells serve as dominant antigen-presenting cells in the induction of T-cell mediated immune responses and subsequent reactivation of T cells. Under homeostatic conditions, however, dendritic cells are primarily involved in the maintenance of immune tolerance to self- and innocuous non-self antigens. T lymphocytes with specificity for antigens penetrating through the skin acquire the propensity, by virtue of the expression of specific homing receptors, to recirculate in the skin. Keratinocytes have the capacity to secrete an array of cytokines and chemokines very important for the regulation of dendritic cell functions, and the recruitment and activation of inflammatory cells; in addition, keratinocytes can directly modulate T cell activation by expressing on their surface adhesion molecules and major histocompatibility complex class II molecules. Mast cells and peptidergic nerve endings form an integrated unit which can readily release factors involved in the initiation of the vascular phase of acute inflammation, but, together with endothelial cells, they also regulate cell-mediated immune responses.

Emerging evidence indicates that physiologically relevant thermal stress regulates dendritic cell function.

Elevations in temperature that are associated with inflammation or fever have been linked to improved survival from infections, enhanced immunological functions, and increased control of tumor growth. Over the past few years, several groups have begun to explore the possible linkage among these observations and have tested the hypothesis that various immune cells are especially sensitive to thermal stimulation. However, relatively little is known regarding the effects of thermal stimulation on antigen presenting cells (APCs), such as dendritic cells (DCs). Very recently, several groups have begun to examine the ability of thermal stimuli to regulate the function of these cells which are known to play a pivotal role in the efficacy of vaccines and other immunotherapies. In this review, we summarize what has been discovered about the role of mild thermal stress in regulating various Dendritic cell (DC) activities. Excitingly, it appears that mild elevations of temperature have the potential to enhance antigen uptake, activation associated migration, maturation, cytokine expression and T cell stimulatory activity of DCs. While these studies reveal that the timing, temperature and duration of heating is important, they also set the stage for essential questions that now need to be investigated regarding the molecular mechanisms by which elevated temperatures regulate DC function. With this information, we may soon be able to maximize the strategic use of thermal therapy as an adjuvant, i.e., combining its use with cancer immunotherapies such as vaccines, which depend upon the function of DCs. Several possible strategies and timepoints involving the clinical application of hyperthermia in combination with immunotherapy are presented.

Regulation of Dendritic Cell Function with Immunomodulatory Drugs

Dendritic cells (DC) represent a sentinel-like system with the capacity to capture and process antigens, to migrate into secondary lymphoid organs, and to activate naive T lymphocytes. DCs are considered as important elements in the induction of specific immune responses. The potency of DCs for induction of immune responses can be affected by a number of aspects related to their maturation stage and state of activation. For a long time, the critical role of DCs in many clinical situations was underscored. DCs in vivo might represent a favored target for immune tolerance (cancer) or immune activation (auto-immune diseases and allergic hypersensitivity). For immunotherapeutic applications, it is crucial to identify factors and agents that might affect the differentiation, maturation and function of DCs. This review will focus on the impact of the most widely used immunomodulatory drugs in the clinical setting on the properties and functions of DCs. The modulation and manipulation of DC functions through exposure of DCs to immunomodulatory agents both in vitro and in vivo is an approach that could result in therapeutic benefit in many clinical situations. Keywords: dendritic cells, immunomodulation, tolerance, immunostimulation, cytokines

Immunopathogenesis of type C hepatitis: dendritic cell in HCV infection

Abstract Dendritic cells (DCs) are professional antigen‐presenting cells that enhance and regulate both innate and acquired immune reactions. It has been reported that several viruses actively down regulate DC function to escape from host immune system. To clarify the involvement of DC in anti‐hepatitis C virus (HCV) immune reactions, we compared DC function between chronic hepatitis C patients and healthy donors. Monocyte‐derived DCs generated from patients were relatively immature and were impaired in allostimulatory capacity and IL‐12 p70 production when compared to that from donors. In addition, MDC and PDC in HCV‐infected patients were reduced in number and impaired in their ability to promote Th1 polarization. These results demonstrate that DCs are numerically and functionally impaired in HCV‐infected patients, which is critically involved in the pathogenesis and persistence of HCV infection.

PPAR-gamma Agonists Inhibit Toll-Like Receptor Mediated Activation of Dendritic Cells Via the MAP Kinase and NF-kB Pathways.

Dendritic cells (DC) play an important role in initiating and maintaining of primary immune responses. However, little is known about the termination of once induced immunological responses. Cyclopentenone prostaglandins (15d-PGJ2, PGD2) are produced during the late phase of inflammation due to upregulation of COX2 and can lead to the resolution of an inflammation by activation of PPAR-gamma dependent and independent pathways. In this study we analyzed the effects of 15d-PGJ2 and the synthetic PPAR-gamma ligand troglitazone (TGZ) on the immunogenicity of monocyte derived DC upon stimulation with toll-like receptor (TLR) ligands. Activation of PPAR-gamma resulted in a reduced activation of DC via the TLR ligands 2, 3, 4 and 7 characterized by downregulation of CD83, adhesion and costimulatory molecules. Moreover, these cells secreted lower levels of cytokines and chemokines involved in T lymphocyte activation and recruitment including IL-12 and RANTES. In contrast to these results, MCP-1 production was increased due to the treatment with PPAR-gamma agonists. To determine the mechanisms by which PPAR-gamma regulates DC function we performed Western blot analyses and found that the inhibitory effects on TLR induced DC activation were mediated via inhibition of the NF-kB and MAP kinase pathways. Incubation of DC during the differentiation from monocytes with 15d-PGJ2 or TGZ resulted in downregulation of TLR ligands induced phosphorylation of ERK1 as well as reduced expression of nuclear localized members of the NF-kB family. No effect on the expression of MyD88, an adaptor molecule involved in the signal transduction of TLR, was observed. Our results demonstrate that inhibition of the MAP kinase and NF-kB pathways is critically involved in the regulation of TLR and PPAR-gamma mediated signaling in DC an represent a novel negative feed-back mechanism involved in the resolution of immunological responses.

Turning it on and off: regulation of dendritic cell function in Toxoplasma gondii infection.

Because of its intrinsic virulence, Toxoplasma gondii induces a potent interleukin-12 (IL-12)-dependent cell-mediated immune response that shuts down the growth of the replicative tachyzoite stage, thus promoting host survival and successful transmission through predation. At the same time, this response must be tightly controlled to prevent lethality due to cytokine-mediated immunopathology. Evidence accumulated in recent years suggests that dendritic cells (DCs) play a major role in the initiation of IL-12-driven host resistance and that IL-12 synthesis by DCs is carefully regulated to avoid overproduction. In addition, this work has revealed a critical role for DCs in determining the highly polarized T-helper 1 (Th1)-type response triggered by the parasite. In this review, we summarize our current understanding of how DC function is initiated by Toxoplasma and how parasite-primed DCs drive Th1 effector choice. In addition, we discuss recent findings concerning the pathways responsible for endogenous regulation of DC IL-12 production during T. gondii infection.

Regulation of dendritic cell function by NK cells: mechanisms underlying the synergism in the combination therapy of IL-12 and 4-1BB activation.

The interactions between NK cells and dendritic cells (DCs) have been previously demonstrated in vitro. In this report, the in vivo cross-regulation between NK cells and DCs was studied in tumor-bearing mice treated with adenoviral vector expressing IL-12 and agonistic anti-4-1BB Abs. NK cells are essential for both tumor rejection and CTL development in the combination therapy (IL-12 plus anti-4-1BB). The numbers and functional activities of both NK cells and DCs in tumor-infiltrating leukocytes were synergistically increased in the IL-12 plus anti-4-1BB-treated mice compared with treatment with either reagent alone. NK depletion in vivo resulted in a significant decrease in the number of DCs in tumor-infiltrating leukocytes, strongly suggesting that NK cells are involved in the activation and expansion of DCs. The mechanism by which IL-12-activated NK cells regulate DC functions is, in part, mediated through the secretion of IFN-gamma that leads to the up-regulation of 4-1BB by DCs. Furthermore, 4-1BB activation in conjunction with IL-12 gene delivery increased tumor infiltration of green fluorescence protein-labeled DCs and enhanced their MHC class II expression. The activation of DCs by NK cells and the subsequent development of antitumoral CTL responses facilitated by 4-1BB-activated DCs may account for the synergistic effects observed in the combination therapy in comparison to adenoviral vector expressing IL-12 or anti-4-1BB treatment alone.

Pneumatocoele formation during Pneumocystis carinii pneumonia in a man with HIV-1 infection

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