Dendritic cells are involved in the initiation of both innate and adaptive immunity. To systematically explore how dendritic cells modulate the immune system in response to different pathogens, we used oligonucleotide microarrays to measure gene expression profiles of dendritic cells in response to Escherichia coli, Candida albicans, and influenza virus as well as to their molecular components. Both a shared core response and pathogen-specific programs of gene expression were observed upon exposure to each of these pathogens. These results reveal that dendritic cells sense diverse pathogens and elicit tailored pathogen-specific immune responses.

IntroductionHistone-modifying enzymes, such as histone acetyltransferases (HATs) and histone deacetylases (HDACs), are critical in controlling the dynamics of chromatin structure and function by regulating histone acetylation. This process is essential in modulating gene transcription through chromatin organization, and plays an important role in many key biological processes. 1 The perturbation of this process results in aberrant gene transcription and causes neoplasia and other diseases. 2 In general, increased histone acetylation is associated with transcription activation through relaxed chromatin structure, whereas decreased histone acetylation is associated with repression of transcription via chromatin condensation. Recently, an increasing number of nonhistone proteins such as p53, HSP90, and STAT3, for example, have been identified as substrates of HDACs, indicating a novel mechanism of action of HDACs in modulating gene function. 3 The classical HDAC gene family consists of 11 members, which fall into 2 classes. Class I HDACs (HDAC1, HDAC2, HDAC3, and HDAC8) are expressed ubiquitously, whereas the expression of class II HDACs (HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, and HDAC10) is more restricted. 4 Small molecules capable of inhibiting both class I and II HDAC activities, such as suberoylanilide hydroxamic acid (SAHA), trichostatin (TSA), trapoxin, and others, induce general histone acetylation, and are promising anticancer agents. 3,5 In addition to their anticancer activities, several HDAC inhibitors (HDACi's) have been shown to be effective in selected immune disease models. For example, SAHA has been shown to reduce graft-versushost disease (GVHD) in a murine model of bone marrow transplantation 6 and block renal disease in MRL-lpr/lpr mice 7 ; TSA suppressed adjuvant-induced rheumatoid arthritis (RA) in rats 8 and reduced clinical symptoms in a murine model of multiple sclerosis (MS). 9 However, little is known about the cellular and molecular mechanisms governing the in vivo effects of HDACi's in these autoimmune models. Therefore, we set out to systematically investigate the cellular effects of LAQ824, a novel hydroxamic acid derivative with demonstrated clinical efficacy as an HDAC pan-inhibitor, 5,10 in immune responses, and to suggest a mechanistic rationale for using HDACi's in inflammatory diseases.Chronic inflammation is a physiologic state that underlies many diseases. 11 The inflammation cascade is usually initiated by immune or stress responses to environmental or endogenous stimuli, and it is tightly controlled by the activation and silencing of differentially expressed genes. Professional antigen-presenting cells (APCs), particularly macrophages and dendritic cells (DCs), are central players in the initiation of an inflammation cascade. They are the first line of defense in that they respond to diverse antigens, secrete cytokines and chemokines, modulate the expression of costimulatory molecules, and thereby instruct other innate and adaptive immune cells to mount appropriate responses. 12...

Immature dendritic cells are among the first cells infected by retroviruses after mucosal exposure. We explored the effects of human immunodeficiency virus-1 (HIV-1) and its Tat transactivator on these primary antigen-presenting cells using DNA microarray analysis and functional assays. We found that HIV-1 infection or Tat expression induces interferon (IFN)-responsive gene expression in immature human dendritic cells without inducing maturation. Among the induced gene products are chemokines that recruit activated T cells and macrophages, the ultimate target cells for the virus. Dendritic cells in the lymph nodes of macaques infected with simian immunodeficiency virus (SIV) have elevated levels of monocyte chemoattractant protein 2 (MCP-2), demonstrating that chemokine induction also occurs during retroviral infection in vivo. These results show that HIV-1 Tat reprograms host dendritic cell gene expression to facilitate expansion of HIV-1 infection.

Osteosarcoma (OS), which occurs most commonly in adolescents, is associated with a high degree of malignancy and poor prognosis. In order to develop an accurate treatment for OS, a deeper understanding of its complex tumor microenvironment (TME) is required. In the present study, tissues were isolated from six patients with OS, and then subjected to single-cell RNA sequencing (scRNA-seq) using a 10× Genomics platform. Multiplex immunofluorescence staining was subsequently used to validate the subsets identified by scRNA-seq. ScRNA-seq of six patients with OS was performed prior to neoadjuvant chemotherapy, and data were obtained on 29,278 cells. A total of nine major cell types were identified, and the single-cell transcriptional map of OS was subsequently revealed. Identified osteoblastic OS cells were divided into five subsets, and the subsets of those osteoblastic OS cells with significant prognostic correlation were determined using a deconvolution algorithm. Thereby, different transcription patterns in the cellular subtypes of osteoblastic OS cells were reported, and key transcription factors associated with survival prognosis were identified. Furthermore, the regulation of osteolysis by osteoblastic OS cells via receptor activator of nuclear factor kappa-B ligand was revealed. Furthermore, the role of osteoblastic OS cells in regulating angiogenesis through vascular endothelial growth factor-A was revealed. C3_TXNIP+ macrophages and C5_IFIT1+ macrophages were found to regulate regulatory T cells and participate in CD8+ T cell exhaustion, illustrating the possibility of immunotherapy that could target CD8+ T cells and macrophages. Our findings here show that the role of C1_osteoblastic OS cells in OS is to promote osteolysis and angiogenesis, and this is associated with survival prognosis. In addition, T cell depletion is an important feature of OS. More importantly, the present study provided a valuable resource for the in-depth study of the heterogeneity of the OS TME.