Blood is the predominant source for molecular analyses in humans, both in clinical and research settings. It is the target for many therapeutic strategies, emphasizing the need for comprehensive ...molecular maps of the cells constituting human blood. In this study, we performed a genome-wide transcriptomic analysis of protein-coding genes in sorted blood immune cell populations to characterize the expression levels of each individual gene across the blood cell types. All data are presented in an interactive, open-access Blood Atlas as part of the Human Protein Atlas and are integrated with expression profiles across all major tissues to provide spatial classification of all protein-coding genes. This allows for a genome-wide exploration of the expression profiles across human immune cell populations and all major human tissues and organs.
Immune-microbe interactions early in life influence the risk of allergies, asthma, and other inflammatory diseases. Breastfeeding guides healthier immune-microbe relationships by providing nutrients ...to specialized microbes that in turn benefit the host’s immune system. Such bacteria have co-evolved with humans but are now increasingly rare in modern societies. Here we show that a lack of bifidobacteria, and in particular depletion of genes required for human milk oligosaccharide (HMO) utilization from the metagenome, is associated with systemic inflammation and immune dysregulation early in life. In breastfed infants given Bifidobacterium infantis EVC001, which expresses all HMO-utilization genes, intestinal T helper 2 (Th2) and Th17 cytokines were silenced and interferon β (IFNβ) was induced. Fecal water from EVC001-supplemented infants contains abundant indolelactate and B. infantis-derived indole-3-lactic acid (ILA) upregulated immunoregulatory galectin-1 in Th2 and Th17 cells during polarization, providing a functional link between beneficial microbes and immunoregulation during the first months of life.
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•An ordered sequence of immune changes after birth driven by microbial interactions•Lack of gut bifidobacteria and HMO-utilization genes correlates with systemic inflammation•Feeding B. infantis EVC001 upregulates IFNβ and silences intestinal Th2 and Th17•EVC001-associated indole-3-lactic acid upregulates inhibitory galectin-1 in T cells
A lack of bifidobacteria and/or their genes required for the utilization of human milk oligosaccharides from breast milk is associated with systemic inflammation and immune imbalance early in life. Infant supplementation of Bifidobacterium infantis EVC001 shows promise in mitigating this by reducing Th2 and Th17 cytokines in the intestine through upregulation of the immunoregulatory factor galectin-1.
All circulating immunoglobulin G (IgG) antibodies in human newborns are of maternal origin
and transferred across the placenta to provide passive immunity until newborn IgG production takes over 15 ...weeks after birth
. However, maternal IgG can also negatively interfere with newborn vaccine responses
. The concentration of IgG increases sharply during the third trimester of gestation and children delivered extremely preterm are believed to largely lack this passive immunity
. Antibodies to individual viruses have been reported
, but the global repertoire of maternal IgG, its variation in children, and the epitopes targeted are poorly understood. Here, we assess antibodies against 93,904 epitopes from 206 viruses in 32 preterm and 46 term mother-child dyads. We find that extremely preterm children receive comparable repertoires of IgG as term children, albeit at lower absolute concentrations and consequent shorter half-life. Neutralization of the clinically important respiratory syncytial virus (RS-virus) was also comparable until three months of age. These findings have implications for understanding infectious disease susceptibility, vaccine development, and vaccine scheduling in newborn children.
The role of tryptophan-kynurenine metabolism in psychiatric disease is well established, but remains less explored in peripheral tissues. Exercise training activates kynurenine biotransformation in ...skeletal muscle, which protects from neuroinflammation and leads to peripheral kynurenic acid accumulation. Here we show that kynurenic acid increases energy utilization by activating G protein-coupled receptor Gpr35, which stimulates lipid metabolism, thermogenic, and anti-inflammatory gene expression in adipose tissue. This suppresses weight gain in animals fed a high-fat diet and improves glucose tolerance. Kynurenic acid and Gpr35 enhance Pgc-1α1 expression and cellular respiration, and increase the levels of Rgs14 in adipocytes, which leads to enhanced beta-adrenergic receptor signaling. Conversely, genetic deletion of Gpr35 causes progressive weight gain and glucose intolerance, and sensitizes to the effects of high-fat diets. Finally, exercise-induced adipose tissue browning is compromised in Gpr35 knockout animals. This work uncovers kynurenine metabolism as a pathway with therapeutic potential to control energy homeostasis.
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•Kynurenic acid increases energy expenditure by activating Gpr35•Gpr35 activation improves energy metabolism and inflammation in mice fed a high-fat diet•Kynurenic acid enhances adipocyte beta-adrenergic receptor signaling through Rgs14•Gpr35 knockout compromises exercise-induced adipose tissue browning
Kynurenine is a neurotoxic metabolite detoxified to kynurenic acid by exercised skeletal muscle. Now, Agudelo et al. show that the rise in circulating kynurenic acid activates Gpr35 in adipose tissue and increases energy expenditure. This improves the metabolic consequences of high-fat diet feeding in mice. Gpr35 deletion causes progressive weight gain.
Using mass cytometry, we investigated the expression of 28 markers on CD8+ and CD4+ T cells from HIV-1 infected patients with a variable size of HIV-1 reservoir defined as high (HR) and low (LR) ...reservoir; we aimed at identifying phenotypic associations of T cells with size of HIV-1 reservoir. We showed that the frequency of CD45+ CD8+ and CD4+ T cells was directly proportional to the size of HIV-1 reservoir; HR patients had a significantly larger frequency of blood CD45
T cells and higher CD45 expression on both CD8+ and CD4+ T cells. CD45 is a receptor-type protein tyrosine phosphatase essential in TCR signaling. Functional and phenotypical analysis of CD45
cells revealed that they express activation and proliferation markers (CD38 + HLA-DR + and Ki-67) and produce cytokines upon in vitro activation. CD45
T cells also expressed high levels of immune check-point PD-1. Our results link CD45 expression on T cells to HIV-1 reservoir; PD-1 expression on CD45
T cells may contribute to their exhaustion.
An important aspect of precision medicine is to probe the stability in molecular profiles among healthy individuals over time. Here, we sample a longitudinal wellness cohort with 100 healthy ...individuals and analyze blood molecular profiles including proteomics, transcriptomics, lipidomics, metabolomics, autoantibodies and immune cell profiling, complemented with gut microbiota composition and routine clinical chemistry. Overall, our results show high variation between individuals across different molecular readouts, while the intra-individual baseline variation is low. The analyses show that each individual has a unique and stable plasma protein profile throughout the study period and that many individuals also show distinct profiles with regards to the other omics datasets, with strong underlying connections between the blood proteome and the clinical chemistry parameters. In conclusion, the results support an individual-based definition of health and show that comprehensive omics profiling in a longitudinal manner is a path forward for precision medicine.
Natural killer (NK) cells express inhibitory receptors for major histocompatibility complex (MHC) class I. If self-MHC is down-regulated or absent, lack of inhibition triggers “missing self” killing. ...NK cells developing in the absence of MHC class I are hypo-responsive, demonstrating that MHC class I molecules are required for NK-cell education. Here, we show that the number and the type of MHC class I alleles that are present during NK-cell education quantitatively determine the frequency of responding NK cells, the number of effector functions in individual NK cells, and the amount of interferon-γ production in NK cells of specific Ly49 subsets. A relationship between the extent of inhibitory signals during education and functional responsiveness was corroborated by an enhanced probability of NK cells expressing more than one inhibitory receptor for a single host self–MHC class I allele to degranulate after activation. Our data suggest that the capacity of an individual NK cell to respond to stimulation is quantitatively controlled by the extent of inhibitory signals that are received from MHC class I molecules during NK-cell education.
Severe disease of SARS-CoV-2 is characterized by vigorous inflammatory responses in the lung, often with a sudden onset after 5–7 days of stable disease. Efforts to modulate this hyperinflammation ...and the associated acute respiratory distress syndrome rely on the unraveling of the immune cell interactions and cytokines that drive such responses. Given that every patient is captured at different stages of infection, longitudinal monitoring of the immune response is critical and systems-level analyses are required to capture cellular interactions. Here, we report on a systems-level blood immunomonitoring study of 37 adult patients diagnosed with COVID-19 and followed with up to 14 blood samples from acute to recovery phases of the disease. We describe an IFNγ-eosinophil axis activated before lung hyperinflammation and changes in cell-cell co-regulation during different stages of the disease. We also map an immune trajectory during recovery that is shared among patients with severe COVID-19.
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Immunomonitoring from acute to recovery phase COVID-19An IFNγ-eosinophil axis precedes lung hyperinflammationBasophils modulate SARS-CoV-2 IgG responsesA shared trajectory of immunological recovery in COVID-19
Immune dysregulation plays a pivotal role during severe COVID-19. Rodriguez et al. present a systems-level, longitudinal study of 37 COVID-19 patients monitored from acute to recovery phases of disease. This study reveals cell-protein dependencies and co-regulated features, as well as a shared immunological trajectory during recovery.
Human immune systems are variable, and immune responses are often unpredictable. Systems-level analyses offer increased power to sort patients on the basis of coordinated changes across immune cells ...and proteins. Allogeneic stem cell transplantation is a well-established form of immunotherapy whereby a donor immune system induces a graft-versus-leukemia response. This fails when the donor immune system regenerates improperly, leaving the patient susceptible to infections and leukemia relapse. We present a systems-level analysis by mass cytometry and serum profiling in 26 patients sampled 1, 2, 3, 6, and 12 months after transplantation. Using a combination of machine learning and topological data analyses, we show that global immune signatures associated with clinical outcome can be revealed, even when patients are few and heterogeneous. This high-resolution systems immune monitoring approach holds the potential for improving the development and evaluation of immunotherapies in the future.
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•Mass cytometry data analysis after allogeneic stem cell transplantation•Perturbed co-regulation patterns of cells and proteins are associated with complications•Topological data analyses allow for the integration of cell, protein, and metadata•Cytomegalovirus has a profound impact on the regenerating immune system
Lakshmikanth et al. conduct a systems analysis of immune reconstitution after stem cell transplantation. Using topological data analysis, combinations of cells and proteins associated with CMV and graft-versus-host disease were revealed and illustrate the potential of systems immunomonitoring to improve the development and evaluation of cancer immunotherapies.
NK cells use a variety of receptors to detect abnormal cells, including tumors and their metastases. However, in the case of melanoma, it remains to be determined what specific molecular interactions ...are involved and whether NK cells control metastatic progression and/or the route of dissemination. Here we show that human melanoma cell lines derived from LN metastases express ligands for natural cytotoxicity receptors (NCRs) and DNAX accessory molecule-1 (DNAM-1), two emerging NK cell receptors key for cancer cell recognition, but not NK group 2 member D (NKG2D). Compared with cell lines derived from metastases taken from other anatomical sites, LN metastases were more susceptible to NK cell lysis and preferentially targeted by adoptively transferred NK cells in a xenogeneic model of cell therapy. In mice, DNAM-1 and NCR ligands were also found on spontaneous melanomas and melanoma cell lines. Interference with DNAM-1 and NCRs by antibody blockade or genetic disruption reduced killing of melanoma cells. Taken together, these results show that DNAM-1 and NCRs are critical for NK cell-mediated innate immunity to melanoma cells and provide a background to design NK cell-based immunotherapeutic strategies against melanoma and possibly other tumors.
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