Dendritic cells but not macrophages are targets for immune regulation by natural killer cells

Both dendritic cells (DC) and macrophages (M phi) stimulate lymphocyte proliferation in secondary mixed-lymphocyte (ML) reactions, though DC are approximately fourfold more effective. Natural killer (NK) cells suppress secondary ML reactions when DC are used, but NK cells do not suppress when M phi are used in these reactions. The findings are consistent with the idea that DC, but not M phi, are potential targets in immune regulation mediated by NK cells.     

Homeostasis of intestinal immune regulation

Regulatory CD4 T cells with the capacity to inhibit potentially harmful immune responses have been described in various experimental systems. Although the observations are converging towards the naturally activated CD25(+) CD4 T cells as a major population responsible for this protection, there is still considerable disagreement on the molecular and cellular requirements involved to achieve a stable immune homeostasis in vivo.     

Dendritic cells in the recognition of intestinal microbiota

Mucosal dendritic cells (DCs) constantly survey the luminal microenvironment which contains commensal microbiota and potentially harmful organisms regulating pathogen recognition and adaptive as well as innate defense activation. Distinct mechanisms are beginning to emerge by which intestinal antigen sampling and handling is achieved ensuring specificity and contributing to redundancy in pathogen detection. Distinct DC subsets are associated with these mechanisms and regulate specific innate or adaptive immune responses to help distinguish between commensal microbiota, pathogens and self antigens. Understanding DC biology in the mucosal immune system may contribute to the unraveling of infection routes of intestinal pathogens and may aid in developing novel vaccines and therapeutic strategies for the treatment of infectious and inflammatory diseases.     

Dendritic cells in innate immune responses against HIV

Dendritic cells (DCs) were recently found to be innate immunity effectors against tumoral cells and viruses. (i) In response to most viruses, including HIV, plasmacytoid DCs are responsible for most of the type I IFN secretion, which is strongly anti-viral and induces TH1 type responses. Myeloid DCs secrete IL-12, which is also important for TH1-type and cytotoxic responses. In HIV patient blood, both DC population numbers decrease as early as the primary stage. Plasmacytoid DC numbers correlate with type I IFN secretion, which is a prognosis predictor, particularly under treatment. IL-12 secretion is also defective. Immunotherapies to replace the defective cytokines or to restore a potentially defective DC-T lymphocyte feed-back might help patients restore their immune responses under antiviral therapy. (ii) After measles and other viral infections, or incubation with dsRNA, DCs become cytotoxic and consequently exhibit natural killer function, through upregulation of type I IFN secretion which enhances TRAIL expression. In HIV infection, this mechanism was not demonstrated yet, but it might a) be responsible for the massive apoptosis of uninfected lymphocytes, and b) increase specific immunity through cross-presentation of antigens from infected cells killed by DCs. (iii) DCs direct expansion and effector functions of NK cells in the absence of adaptive-type cytokines and modulate NKT cell IFN-gamma production. Reciprocally, NK activation triggers DC maturation. HIV-1 Tat inhibits NK cell cytotoxicity directly and probably through inhibition of IL-12 secretion by DC. Therefore, understanding the functions of DCs in innate immune responses and in pathogenesis will help obtain better HIV replication control.     

肠道菌群在机体免疫调节功能中的作用

肠道菌群被称为是人体的一个重要"器官",具有数量庞大、种类繁多等特点,对人体具有重要的生理与病理意义。肠道菌群对机体免疫功能的影响日益受到广泛关注。本文主要就肠道菌群对肠道形态及功能、肠道黏膜免疫系统以及肠道外免疫系统三个方面的影响进行综述。     

Dendritic cells and cytokines in immune rejection of cancer

Dendritic cells (DCs) play a crucial role in linking innate and adaptive immunity and, thus, in the generation of a protective immune response against both infectious diseases and tumors. The ability of DCs to prime and expand an immune response is regulated by signals acting through soluble mediators, mainly cytokines and chemokines. Understanding how cytokines influence DC functions and orchestrate the interactions of DCs with other immune cells is strictly instrumental to the progress in cancer immunotherapy. Herein, we will illustrate how certain cytokines and immune stimulating molecules can induce and sustain the antitumor immune response by acting on DCs. We will also discuss these cytokine-DC interactions in the light of clinical results in cancer patients.     

Dendritic cells in colorectal cancer correlate with other tumor-infiltrating immune cells

Dendritic cells (DCs) are the most efficient antigen-presenting cells and play a key role in a cellular antitumor immune response. In this study we investigated the exact localization of DCs within colorectal tumors and their relationship to tumor-infiltrating lymphocytes as well as clinical outcome of the patients. Primary tumor specimens of 104 patients with a diagnosis of colorectal cancer were identified retrospectively and analyzed with the dendritic cell markers S-100 protein and human leukocyte antigens (HLA) class II. The markers were individually combined with laminin as a second marker to facilitate the observation of the different tumor localizations. S-100 or HLA class II positive cells were found in the three different compartments of colorectal tumors: tumor epithelium, tumor stroma, and advancing tumor margin, but mainly present in tumor stroma and advancing tumor margin. S-100-positive tumor-infiltrating DCs in direct contact with tumor cells, i.e., in tumor epithelium, significantly correlated to the intraepithelial infiltration of CD4+ (p=0.02) and CD8+ (p=0.01) lymphocytes. High HLA class II+ cell infiltration in the tumor stroma correlated to a lower intraepithelial infiltration of CD8+ (p=0.02) lymphocytes. High intraepithelial infiltration of S-100-positive DCs suggested increased disease-free survival, but was not statistically significant, while high amounts of HLA class II+ cells in the tumor stroma correlated with an adverse survival outcome. Our results show that the infiltration of DCs in colorectal cancer, depending on both location and type of marker, is correlated with local immune interactions and patient prognosis, suggesting a central role for DCs in controlling local tumor immunity.     

Dendritic cells and their role in immune reactions of atherosclerosis

Dendritic cells were discovered and recognized as antigen-presenting cells in 1973. Since then, a large volume of information has been accumulated showing the role of dendritic cells as a key element connecting the innate and adaptive immunity. Today, dendritic cells are considered to be dedicated sensors of the immune system that are capable of recognizing both antigen amounts and antigen persistence via complex mechanisms that involve decoding and integration of various signals received in a receptor-dependant manner. The tissue microenvironment plays an important role in the modulation of effector functions of dendritic cells, inducing either activation or suppression of immune reactions. Dendritic cells maintain homeostasis and are involved in a number of diseases, including infectious diseases and cancer. The presence of dendritic cells in arteries was reported in 1995, and, since then, the involvement of dendritic cells in atherogenesis has been evaluated. This review briefly describes the current knowledge of dendritic cells and their role in atherosclerosis.     

细菌耐药影响肠道菌群及其宿主免疫调控

抗生素在养殖业、医疗业及制药业的广泛应用导致环境中的细菌耐药性日益严重,环境中的抗生素及耐药细菌一旦进入人体肠道,将破坏肠道菌群稳态,对人体健康造成威胁,而残存于饮食中的环境污染物则加剧了细菌耐药造成的人体健康影响。文中在总结大量文献的基础上,阐述了细菌耐药对人体和动物肠道菌群的影响机制及其相关的机体免疫调控,以环境中影响人体肠道菌群获得耐药性的来源作为切入点,阐述抗生素和耐药细菌进入人体肠道后对人体肠道菌群结构和耐药基因组成的影响,以及与人体免疫和免疫调节相关疾病之间的相关机制,并对今后的研究方向进行了展望。     

Dendritic cells amplify T cell-mediated immune responses in the central nervous system

Neuroinflammation often starts with the invasion of T lymphocytes into the CNS leading to recruitment of macrophages and amplification of inflammation. In this study, we show that dendritic cells (DCs) facilitate T-T cell help in the CNS and contribute to the amplification of local neuroinflammation. We adoptively transferred defined amounts of naive TCR-transgenic (TCR) recombination-activating gene-1-deficient T cells into another TCR-transgenic mouse strain expressing different Ag specificity. Following adoptive transfers, we coinjected DCs that presented one or multiple Ags into the brain and followed the activation of T cells with defined specificities simultaneously. Injection of DCs presenting both Ags simultaneously led to significantly higher infiltration of T cells into the brain compared with injection of a mixture of DCs pulsed with two Ags separately. DCs mediated either cooperative or competitive interactions between T cell populations with different specificities depending upon their MHC-restricting element usage. These results suggest that DC-mediated cooperation between brain-infiltrating T cells of different Ag specificities in the CNS plays an important role in regulation of neuroinflammation. This work also implies that blocking Ag-specific responses may block not only the targeted specificities, but may also effectively block their cooperative assistance to other T cells. Therefore, these data justify more attention to Ag-specific therapeutic approaches for neuroinflammation.     

肠粘膜上皮细胞在天然免疫中的作用

粘膜免疫是机体防御系统的主要成分。致病性细菌侵入机体后,首先遭遇到天然免疫的抵抗,随后产生获得性免疫,两共同执行机体的防御功能,消灭入侵细菌。最近的研究表明上皮细胞对细菌感染有重要的免疫调节作用,在天然免疫与获得性免疫防御机制中起重要作用。本重点介绍肠上皮细胞在天然免疫中的作用。     

Dendritic cells as natural adjuvants and modulators of immune response in cancer immunotherapy

Dendritic cells (DCs) are potent antigen presenting cells. Mature DCs activate antigen specific na?ve T cells, B cells and NK cells. Under certain conditions, DCs even silence T cell immune responses in vivo, thus, modulating the immune response. This special function of DCs could be exploited in the treatment of cancer, autoimmune disorder and chronic viral infections.     

Dendritic cells in the induction of protective and nonprotective anticryptococcal cell-mediated immune responses

Dendritic cells (DC) can be divided into three subsets, Langerhans cells, myeloid DC (MDC), and lymphoid DC (LDC), based upon phenotypic and functional differences. We hypothesized that different DC subsets are associated with the development of protective vs nonprotective cell-mediated immune (CMI) responses against the fungal pathogen, Cryptococcus neoformans. To test this, mice were immunized with protective and/or nonprotective immunogens, and DC subsets in draining lymph nodes were assessed by flow cytometry. The protective immunogen (cryptococcal culture filtrate Ag-CFA), in contrast to the nonprotective immunogen (heat-killed cryptococci-CFA), the nonprotective immunogen mixed with the protective immunogen (cryptococcal culture filtrate Ag + heat-killed cryptococci-CFA), or controls, stimulated significant increases in total leukocytes, Langerhans cells, MDC, LDC, and activated CD4+ T cells in draining lymph nodes. The protective immune response resulted in significantly increased levels of anticryptococcal delayed-type hypersensitivity reactivity and activated CD4+ T cells at the delayed-type hypersensitivity reaction site. Draining lymph node LDC:MDC ratios induced by the protective immunogen were significantly lower than the ratios induced by either immunization in which the nonprotective immunogen was present. In contrast, mice given the nonprotective immunogen had LDC:MDC ratios similar to those of naive mice. Our data indicate that lymph node Langerhans cells and MDC are APC needed for induction of the protective response. The predominance of LDC in mice undergoing nonprotective responses suggests that lymph node LDC, like splenic LDC, are negative regulators of CMI responses. In addition to showing DC subsets associated with functional differences, our data suggest that the LDC:MDC balance, which can be modulated by the Ag, determines whether protective or nonprotective anticryptococcal CMI responses develop.     

Shiga toxins activate translational regulation pathways in intestinal epithelial cells

Shiga toxins (Stxs) cause irreversible damage to eukaryotic ribosomes, yet cellular intoxication of intestinal epithelial cells (IECs) results in increased synthesis of selected proteins, notably cytokines. How mRNA translation is maintained in this circumstance is unclear. This study was designed to assess whether Stx-induced alterations in host signal transduction machinery permit translation despite protein synthesis inhibition. A key step of translation is recruitment of initiation machinery to the 5' mRNA cap. This event occurs in part via interaction of the 5' cap with the cap binding protein, eIF4E, whose activity is positively regulated by phosphorylation and negatively regulated by binding to the translational repressor 4E-BP1. Following Stx treatment of IECs, eIF4E phosphorylation was detected by Western blotting using phospho-specific antibodies. Treatment with the p38 inhibitor, SB202190, or either of the ERK1/2 inhibitors, PD98059 and U0126, partially blocked Stx1-induced eIF4E phosphorylation. The Mnk1 inhibitor, CGP57380, blocked both basal and Stx-induced eIF4E phosphorylation. Interestingly, pretreatment with CGP57380 did not alter basal protein synthesis, but diminished the ability of cells to maintain translation following Stx1 challenge. Stx1 also induced hyperphosphorylation of 4E-BP1 and phosphorylation of S6Kinase; both effects were blocked by rapamycin. These data are novel observations showing that Stxs regulate multiple signal transduction pathways controlling translation in host cells, and support a role for eIF4E phosphorylation in maintaining host cell translation despite ribosomal intoxication.     

Dendritic cells in glomerulonephritis

Renal biopsies (n = 45) from patients with various forms of glomerulonephritis (GN), comprising mesangial IgA-GN (n = 25), focal glomerular sclerosis (n = 13) and acute GN (n = 7), were examined by double staining immunocytochemistry (APAAP, streptavidinperoxidase) using unconjugated monoclonal antibodies (Ab) against (i) the CD1b antigen expressed on dendritic cells (DCs), (ii) the invariant chain (Ii), and (iii) biotin-conjugated Ab against HLA-DR. In normal control kidneys (n = 7) without interstitial inflammation, CD1b-positive DCs were not detected. Glomerular endothelial cells and a few cells in mesangial areas showed double staining with the Ab against HLA-DR in Ii. In GN without active interstitial inflammation (n = 9), CD1b-positive DCs were not found. In biopsies with interstitial inflammation (n = 36) CDlb-positive DCs were found interspersed among other inflammatory cells. In seven of the biopsies showing IgA-GN DCs were seen in the vicinity of those glomeruli that exhibited either crescents or glomerular sclerosis with splitting of Bowman’s capsule. In proximal tubular epithelial cells de novo expression of HLA-DR/Ii-chain was only seen when DCs were present. We conclude that in different forms of GN: (i) CDlb-positive DCs play an important role in the development of interstitial inflammation, and (ii) their presence may be related to the de novo coexpression of HLA-DR/Ii in tubular epithelial cells, possibly mediated through the production of interferon γ and other cytokines. Supported by the Deutsche Forschungsgemeinschaft (Wa 698/2-1)     

Dendritic cells capture killed tumor cells and present their antigens to elicit tumor-specific immune responses

Due to their capacity to induce primary immune responses, dendritic cells (DC) are attractive vectors for immunotherapy of cancer. Yet the targeting of tumor Ags to DC remains a challenge. Here we show that immature human monocyte-derived DC capture various killed tumor cells, including Jurkat T cell lymphoma, malignant melanoma, and prostate carcinoma. DC loaded with killed tumor cells induce MHC class I- and class II-restricted proliferation of autologous CD8+ and CD4+ T cells, demonstrating cross-presentation of tumor cell-derived Ags. Furthermore, tumor-loaded DC elicit expansion of CTL with cytotoxic activity against the tumor cells used for immunization. CTL elicited by DC loaded with the PC3 prostate carcinoma cell bodies kill another prostate carcinoma cell line, DU145, suggesting recognition of shared Ags. Finally, CTL elicited by DC loaded with killed LNCap prostate carcinoma cells, which express prostate specific Ag (PSA), are able to kill PSA peptide-pulsed T2 cells. This demonstrates that induced CTL activity is not only due to alloantigens, and that alloantigens do not prevent the activation of T cells specific for tumor-associated Ags. This approach opens the possibility of using allogeneic tumor cells as a source of tumor Ag for antitumor therapies.     

Direct interactions between intestinal immune cells and the diet

Comment on: Li Y, et al. Cell. 2011; 147:629-40.