BCG Vaccination in Humans Elicits Trained Immunity via the Hematopoietic Progenitor Compartment.

Induction of trained immunity by Bacille-Calmette-Guérin (BCG) vaccination mediates beneficial heterologous effects, but the mechanisms underlying its persistence and magnitude remain elusive. In this study, we show that BCG vaccination in healthy human volunteers induces a persistent transcriptional program connected to myeloid cell development and function within the hematopoietic stem and progenitor cell (HSPC) compartment in the bone marrow. We identify hepatic nuclear factor (HNF) family members 1a and b as crucial regulators of this transcriptional shift.

Scalable Prediction of Acute Myeloid Leukemia Using High-Dimensional Machine Learning and Blood Transcriptomics.

Acute myeloid leukemia (AML) is a severe, mostly fatal hematopoietic malignancy. We were interested in whether transcriptomic-based machine learning could predict AML status without requiring expert input. Using 12,029 samples from 105 different studies, we present a large-scale study of machine learning-based prediction of AML in which we address key questions relating to the combination of machine learning and transcriptomics and their practical use.

An intrinsic role of IL-33 in T cell-mediated tumor immunoevasion.

Regulatory T (T) cells accumulate into tumors, hindering the success of cancer immunotherapy. Yet, therapeutic targeting of T cells shows limited efficacy or leads to autoimmunity. The molecular mechanisms that guide T cell stability in tumors remain elusive.

Transcriptional Signature Derived from Murine Tumor-Associated Macrophages Correlates with Poor Outcome in Breast Cancer Patients.

Tumor-associated macrophages (TAMs) are frequently the most abundant immune cells in cancers and are associated with poor survival. Here, we generated TAM molecular signatures from K14cre;Cdh1;Trp53 (KEP) and MMTV-NeuT (NeuT) transgenic mice that resemble human invasive lobular carcinoma (ILC) and HER2 tumors, respectively. Determination of TAM-specific signatures requires comparison with healthy mammary tissue macrophages to avoid overestimation of gene expression differences.

β-Glucan-Induced Trained Immunity Protects against Leishmania braziliensis Infection: a Crucial Role for IL-32.

American tegumentary leishmaniasis is a vector-borne parasitic disease caused by Leishmania protozoans. Innate immune cells undergo long-term functional reprogramming in response to infection or Bacillus Calmette-Guérin (BCG) vaccination via a process called trained immunity, conferring non-specific protection from secondary infections. Here, we demonstrate that monocytes trained with the fungal cell wall component β-glucan confer enhanced protection against infections caused by Leishmania braziliensis through the enhanced production of proinflammatory cytokines.

Epigenetic reprogramming of immune cells in injury, repair, and resolution.

Immune cells are pivotal in the reaction to injury, whereupon, under ideal conditions, repair and resolution phases restore homeostasis following initial acute inflammation. Immune cell activation and reprogramming require transcriptional changes that can only be initiated if epigenetic alterations occur. Recently, accelerated deciphering of epigenetic mechanisms has extended knowledge of epigenetic regulation, including long-distance chromatin remodeling, DNA methylation, posttranslational histone modifications, and involvement of small and long noncoding RNAs.

Shiny-Seq: advanced guided transcriptome analysis.

Objective: A comprehensive analysis of RNA-Seq data uses a wide range of different tools and algorithms, which are normally limited to R users only. While several tools and advanced analysis pipelines are available, some require programming skills and others lack the support for many important features that enable a more comprehensive data analysis. There is thus, a need for a guided and easy to use comprehensive RNA-Seq data platform, which integrates the state of the art analysis workflow.

Enzymatic Activity of HPGD in Treg Cells Suppresses Tconv Cells to Maintain Adipose Tissue Homeostasis and Prevent Metabolic Dysfunction.

Regulatory T cells (Treg cells) are important for preventing autoimmunity and maintaining tissue homeostasis, but whether Treg cells can adopt tissue- or immune-context-specific suppressive mechanisms is unclear. Here, we found that the enzyme hydroxyprostaglandin dehydrogenase (HPGD), which catabolizes prostaglandin E (PGE) into the metabolite 15-keto PGE, was highly expressed in Treg cells, particularly those in visceral adipose tissue (VAT). Nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ)-induced HPGD expression in VAT Treg cells, and consequential Treg-cell-mediated generation of 15-keto PGE suppressed conventional T cell activation and proliferation.

Emerging Principles in Myelopoiesis at Homeostasis and during Infection and Inflammation.

Myelopoiesis ensures the steady state of the myeloid cell compartment. Technological advances in fate mapping and genetic engineering, as well as the advent of single cell RNA-sequencing, have highlighted the heterogeneity of the hematopoietic system and revealed new concepts in myeloid cell ontogeny. These technologies are also shedding light on mechanisms of myelopoiesis at homeostasis and at different phases of infection and inflammation, illustrating important feedback loops between affected tissues and the bone marrow.

The Myeloid Cell Compartment-Cell by Cell.

Myeloid cells are a major cellular compartment of the immune system comprising monocytes, dendritic cells, tissue macrophages, and granulocytes. Models of cellular ontogeny, activation, differentiation, and tissue-specific functions of myeloid cells have been revisited during the last years with surprising results; for example, most tissue macrophages are yolk sac derived, monocytes and macrophages follow a multidimensional model of activation, and tissue signals have a significant impact on the functionality of all these cells. While these exciting results have brought these cells back to center stage, their enormous plasticity and heterogeneity, during both homeostasis and disease, are far from understood.

Innate and Adaptive Immune Memory: an Evolutionary Continuum in the Host's Response to Pathogens.

Immunological memory is an important evolutionary trait that improves host survival upon reinfection. Memory is a characteristic recognized within both the innate and adaptive arms of the immune system. Although the mechanisms and properties through which innate and adaptive immune memory are induced are distinct, they collude to improve host defense to pathogens.

Exposure to the gut microbiota drives distinct methylome and transcriptome changes in intestinal epithelial cells during postnatal development.

Background: The interplay of epigenetic processes and the intestinal microbiota may play an important role in intestinal development and homeostasis. Previous studies have established that the microbiota regulates a large proportion of the intestinal epithelial transcriptome in the adult host, but microbial effects on DNA methylation and gene expression during early postnatal development are still poorly understood. Here, we sought to investigate the microbial effects on DNA methylation and the transcriptome of intestinal epithelial cells (IECs) during postnatal development.

Modulation of Myelopoiesis Progenitors Is an Integral Component of Trained Immunity.

Trained innate immunity fosters a sustained favorable response of myeloid cells to a secondary challenge, despite their short lifespan in circulation. We thus hypothesized that trained immunity acts via modulation of hematopoietic stem and progenitor cells (HSPCs). Administration of β-glucan (prototypical trained-immunity-inducing agonist) to mice induced expansion of progenitors of the myeloid lineage, which was associated with elevated signaling by innate immune mediators, such as IL-1β and granulocyte-macrophage colony-stimulating factor (GM-CSF), and with adaptations in glucose metabolism and cholesterol biosynthesis.

Microbiome Influences Prenatal and Adult Microglia in a Sex-Specific Manner.

Microglia are embryonically seeded macrophages that contribute to brain development, homeostasis, and pathologies. It is thus essential to decipher how microglial properties are temporally regulated by intrinsic and extrinsic factors, such as sexual identity and the microbiome. Here, we found that microglia undergo differentiation phases, discernable by transcriptomic signatures and chromatin accessibility landscapes, which can diverge in adult males and females.

Cellular Differentiation of Human Monocytes Is Regulated by Time-Dependent Interleukin-4 Signaling and the Transcriptional Regulator NCOR2.

Human in vitro generated monocyte-derived dendritic cells (moDCs) and macrophages are used clinically, e.g., to induce immunity against cancer.

Bioinformatic Assessment of Macrophage Activation by the Innate Immune System.

Weighted gene co-expression network analysis (WGCNA) allows for the identification and characterization of cell type-specific gene modules in complex transcriptome datasets. Here, we use a microarray dataset of human macrophages comprising 29 conditions and 299 samples generated by differentiation of CD14 monocytes into macrophages followed by in vitro stimulations to identify stimulation-specific gene modules. These gene modules can be used for experimental validation, as well as further bioinformatic analysis to determine key pathways or upstream transcription factors.

A cross-species approach to identify transcriptional regulators exemplified for Dnajc22 and Hnf4a.

There is an enormous need to make better use of the ever increasing wealth of publicly available genomic information and to utilize the tremendous progress in computational approaches in the life sciences. Transcriptional regulation of protein-coding genes is a major mechanism of controlling cellular functions. However, the myriad of transcription factors potentially controlling transcription of any given gene makes it often difficult to quickly identify the biological relevant transcription factors.

Human fetal dendritic cells promote prenatal T-cell immune suppression through arginase-2.

During gestation the developing human fetus is exposed to a diverse range of potentially immune-stimulatory molecules including semi-allogeneic antigens from maternal cells, substances from ingested amniotic fluid, food antigens, and microbes. Yet the capacity of the fetal immune system, including antigen-presenting cells, to detect and respond to such stimuli remains unclear. In particular, dendritic cells, which are crucial for effective immunity and tolerance, remain poorly characterized in the developing fetus.

Mapping the human DC lineage through the integration of high-dimensional techniques.

Dendritic cells (DC) are professional antigen-presenting cells that orchestrate immune responses. The human DC population comprises two main functionally specialized lineages, whose origins and differentiation pathways remain incompletely defined. Here, we combine two high-dimensional technologies-single-cell messenger RNA sequencing (scmRNAseq) and cytometry by time-of-flight (CyTOF)-to identify human blood CD123CD33CD45RA DC precursors (pre-DC).

S100-alarmin-induced innate immune programming protects newborn infants from sepsis.

The high risk of neonatal death from sepsis is thought to result from impaired responses by innate immune cells; however, the clinical observation of hyperinflammatory courses of neonatal sepsis contradicts this concept. Using transcriptomic, epigenetic and immunological approaches, we demonstrated that high amounts of the perinatal alarmins S100A8 and S100A9 specifically altered MyD88-dependent proinflammatory gene programs. S100 programming prevented hyperinflammatory responses without impairing pathogen defense.

New "programmers" in tissue macrophage activation.

Tissue macrophages and monocyte-derived macrophages are under continuous influence from environmental signals that define their activation status. Along these lines, macrophages integrate tissue and stress signals and are specifically programmed by these signals towards a spectrum of functions necessary to fulfill their duty within their particular microenvironment, be it homeostatic tissue function, response to inflammatory pathophysiology, or even resolution of an inflammation. Recent years have seen tremendous progress in our understanding how macrophages at different sites are transcriptionally and epigenetically programmed to execute their diverse tasks throughout the body.