NextImmune2: PhD Training Programme
Individual projects
Project 1: Dirk Brenner: Mitochondrial metabolism: Deciphering new routes to control T cell function
Metabolism plays a critical role in immune cell differentiation, activation, and plasticity. Adjustments in cellular metabolism are often associated with epigenetic changes and alteration of transcriptional programs. This determines the adaptation of immune cells to the respective environment and to their functional state, which in turn ensures a productive immune response. T cells are an integral part of the immune system. Recently, our lab significantly contributed to the understanding how metabolism controls T cell-based immunity (Kurniawan et al. 2020; Mak and Grusdat et al. 2017). The control of T cell metabolism offers a great opportunity to intervene therapeutically with the function of these important immune cells and thus to mitigate detrimental inflammatory diseases including autoimmunity and cancer. A central metabolic regulatory node are the mitochondria. However, our understanding of how mitochondrial metabolism controls T cell function and how it affects different T cell subsets is still incomplete. In this project, we will study mitochondrial metabolism in T cells. We will focus on the manipulation of mitochondrial metabolism with the ultimate aim of obtaining insights into the functional properties of T cells. We will investigate this using genetic altered mouse mutant models in combination with in vivo disease models for autoimmunity and infection and with studies on human T cells. We will conduct a detailed molecular, metabolic and cellular analysis of mitochondrial T cell metabolism that also includes transcriptional, metabolic and epigenetic profiling. The overall aim is to characterize novel metabolic checkpoints in T cells that are of disease relevance.
Kurniawan, H., et al., Glutathione Restricts Serine Metabolism to Preserve Regulatory T Cell Function. Cell Metab, 2020. 31(5): p. 920-936 e7.
Cox, M.A., et al., Choline acetyltransferase-expressing T cells are required to control chronic viral infection. Science, 2019. 363(6427): p. 639-644.
Mak, T.W., et al., Glutathione Primes T Cell Metabolism for Inflammation. Immunity, 2017. 46(4): p. 675-689.
Project 3: Thomas Sauter: Single-cell network modeling of immunometabolism
Single cell profiling techniques are promising for the in-depth characterization of cell types. Such approaches usually yield on enormous amount of data and the subsequent data analysis and knowledge extraction is a key limiting step in biomedical research. Here we propose to develop, benchmark and apply a novel metabolic network modelling pipeline focusing on single cell resolution. The pipeline will take sc-RNA-seq data as input and produce cell-type specific metabolic reconstructions. These will allow to study and characterize on genome-scale the metabolism of identified cell populations individually or in an integrated meta-model. The pipeline will rely on our in-house reconstruction algorithm fastcore which we developed and successfully applied for the reconstruction of compact context-specific metabolic networks based on bulk RNA-seq data and other data types. The respective reconstructed networks allow e.g. to determine disease specific targets and drugs for repositioning. A proof-of-principle sc-version of the algorithm is available, but needs to be further improved and benchmarked on large scale sc-RNA-seq data sets. We will focus on metabolically characterizing the fibroblast and immune cell types closely interacting in chronic inflammation. We aim at identifying unique metabolic markers which will be validated experimentally.
Pacheco, M.P., et al., Identifying and targeting cancer-specific metabolism with network-based drug target prediction. EBioMedicine, 2019. 43: p. 98-106.
Martins Conde, P., et al., A dynamic multi-tissue model to study human metabolism. NPJ Syst Biol Appl, 2021. 7(1): p. 5.
Vlassis, N., M.P. Pacheco, and T. Sauter, Fast reconstruction of compact context-specific metabolic network models. PLoS Comput Biol, 2014. 10(1): p. e1003424.
Project 5: Sabrina Bréchard: Metabolically-rewired stress signaling in melanoma in response to combinatorial immunotherapies.
Advanced melanoma is able to acquire rapid resistance to targeted therapies and immune checkpoint inhibitors. Although it is well established that Ca2+ homeostasis influences tumor growth dynamics, understanding the underlying mechanisms of Ca2+ signaling and their role in response to targeted and/or immunotherapies (IT) is still in its infancy. Another largely unexplored field in tumor biology is the crosstalk between Ca2+ and stress-induced Reactive oxygen species (ROS) signaling and its role in response to therapies. Resistant melanoma is addicted to an oxidative metabolism and presents higher ROS levels. Oxidative stress on the other hand is known to regulate mitochondrial calcium levels.
Our objective is to explore how Ca2+ fluxes can re-wire the cellular metabolome, and how Ca2+ signaling can shape the tumor microenvironment following IT. Using physiological 3D melanoma spheroid models (consisting of melanoma cells, fibroblasts, endothelial and immune cells), we will first determine how Ca2+ fluxes change in response to standard therapies depending on the cellular composition of the multicomponent3D spheroids. Following a combination of targeted/immunotherapy treatments administered under different extracellular Ca2+ conditions, differentially expressed genes as well as metabolite profiles will be assessed in therapy-responding versus -resistant cells with the aim to identify genes and metabolites involved in immune escape pathways.
In parallel, the impact of cellular stressors (inducing e.g. ER-Stress, ROS) on the Ca2+ machinery, metabolites and gene expression in melanoma and immune cells will be analysed to define targets to enhance tumor–targeting immunity. The ultimate objective of this project is to delineate novel drug targets based on Ca2+ and ROS signaling to improve the efficiency of immunotherapy approaches.
Tolle, F., et al., Neutrophils in Tumorigenesis: Missing Targets for Successful Next Generation Cancer Therapies? Int J Mol Sci, 2021. 22(13).
Jung, N., et al., miRNAs Regulate Cytokine Secretion Induced by Phosphorylated S100A8/A9 in Neutrophils. Int J Mol Sci, 2019. 20(22).
Schenten, V., et al., Secretion of the Phosphorylated Form of S100A9 from Neutrophils Is Essential for the Proinflammatory Functions of Extracellular S100A8/A9. Front Immunol, 2018. 9: p. 447.
Project 6: Michael Heneka: Identification of NLRP3 and NLRP1 mediated regulation of microglial immune metabolism in models of again and neurodegeneration
Activation of microglia and subsequent formation of NACHT, LRR and PYD domains-containing protein 3 and 1 have been implicated in aging and neurodegenerative disease. Recent evidence suggests that NLRP3 and NLRP1 have gene regulatory effects that directly connect their assembly to the innate immune metabolism of microglia presumably through the regulation of key elements of the Krebs cycle. In this project, we want to investigate in human iPSC-derived microglia, how NLRP3- and NLRP1-mediated gene regulation influences (i) microglial transcriptomes and (ii) microglial function, which are key for maintaining synaptic integrity and neuronal plasticity. Since microglial senescence has been found to cause tau pathology, a major phenotype of the aging and degenerating brain, we will further study (iii) how NLRP3 and NLRP1 affect microglial senescence and renewal in the respective models.
Ising, C., et al., NLRP3 inflammasome activation drives tau pathology. Nature, 2019. 575(7784): p. 669-673.
Venegas, C., et al., Microglia-derived ASC specks cross-seed amyloid-beta in Alzheimer’s disease. Nature, 2017. 552(7685): p. 355-361.
Heneka, M.T., et al., NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature, 2013. 493(7434): p. 674-8.
Project 7: Anne Grünewald: Leucine-rich repeat kinase 2 at the interface between cellular metabolism and inflammation in microglia from Parkinson’s disease patients
The G2019S mutation in Leucine-rich repeat kinase 2 (LRRK2), which is inherited with reduced penetrance, is the most frequent genetic cause of Parkinson’s disease (PD). LRRK2 is involved in membrane trafficking, autophagy and mitochondrial function. However, albeit the protein is most abundant in immune cells, the majority of mechanistic studies published so far have focused on its relevance in neurons.
The advent of novel iPSC differentiation protocols now allows extending this molecular work towards microglia. We have access to iPSCs from manifesting and non-manifesting G2019S mutation carriers as well as (isogenic) controls. In microglia derived from these lines, we observed a genotype-specific upregulation of LRRK2 and NLPR3. Interestingly, an interplay between the inflammasome and cellular metabolism has previously been described in diabetes, which itself is known to increase PD risk. Based on these findings, we postulate that mutant LRRK2 triggers NLRP3 activation, which in turn disrupts microglia metabolism.
To explore this hypothesis, first, we aim to perform metabolomics in microglia derived from the above-mentioned iPSCs. Second, we will modulate LRRK2 activity by exposing the cells to a kinase inhibitor and determine the impact of this treatment on glial activation and metabolism. Third, we will investigate whether there are metabolic signatures that distinguish manifesting from non-manifesting G2019S carriers. Finally, we will attempt a genetic rescue by targeting key enzymes of the newly established metabolic pathway(s) disrupted in LRRK2-PD.
Badanjak K, M.P., Smajic S, Delcambre S, Tranchevent LC, Diederich N, Rauen T, Schwamborn JC, Glaab E, Cowley SA, Antony P, Pereira S, Venegas C, Grünewald A, IPSC-derived microglia as a model to study inflammation in idiopathic Parkinson’s disease. Front Cell Dev Biol, 2021.
Delcambre, S., et al., Mitochondrial Mechanisms of LRRK2 G2019S Penetrance. Front Neurol, 2020. 11: p. 881.
Borsche, M., et al., Mitochondrial damage-associated inflammation highlights biomarkers in PRKN/PINK1 parkinsonism. Brain, 2020. 143(10): p. 3041-3051.
Project 8: Rejko Krüger: The role of p.D620N VPS35 patient-derived microglia in Parkinson’s Disease pathophysiology
Parkinson’s Disease (PD) is the second most common neurodegenerative disease. One of the genes that is strongly related with PD is VPS35. VPS35, is involved in the intracellular trafficking of the proteins and our group has confirmed that the D620N VPS35 mutation, in patient iPSC-derived dopaminergic neurons (DN), is associated with increased α-synuclein levels due to decrease autophagic flux and significant mitochondrial dysfunction. Recently, another study links VPS35 KO with suppressing microglia polarization, with subsequent accumulation of neurotoxic pro-inflammatory microglia, in ischemic stroke-induced injury mouse model.
Our project proposal is the identification of the role of D620N VPS35 mutation in patient iPSC-derived microglia’s metabolism, the role in PD’s pathophysiology, the confirmation of the mechanism of action and the proposal of a putative co-treatment, based on our results. For this reason, 1) D620N VPS35 mutated iPSCs will be differentiated into functional microglia, in order to characterize the microglial phenotype (cell viability, cytokines production, metabolite quantification/secretosome, phagocytosis efficiency-response to α-synuclein aggregation, mitochondrial/lysosomal function, transcriptomic analysis and exosomal studies), 2) D620N VPS35 mutated iPSC-derived microglia will be co-culture with DN, in order to identify the alterations in the phenotype/metabolism of both cell types, the signaling interaction and the impact of the exosomes in each cell type. Finally, based on our findings, there will be identified new ‘’signature’’- pathways-molecules, that will serve as targets for an innovative co-treatment against PD and their efficiency will be evaluated based on the phenotypic studies (mentioned above).
Boussaad, I., et al., Integrated, automated maintenance, expansion and differentiation of 2D and 3D patient-derived cellular models for high throughput drug screening. Sci Rep, 2021. 11(1): p. 1439.
Boussaad, I., et al., A patient-based model of RNA mis-splicing uncovers treatment targets in Parkinson’s disease. Sci Transl Med, 2020. 12(560).
Hanss, Z., et al., Quality Control Strategy for CRISPR-Cas9-Based Gene Editing Complicated by a Pseudogene. Front Genet, 2019. 10: p. 1297.
Project 9: Jens Schwamborn: Deciphering microglia metabolism and neuronal homeostasis in type 2 diabetes
Recent evidence have shown a strong relationship between the immune system and metabolic disorder. Type 2 diabetes is a metabolic disorder with various immunopathology preceding its development. Interestingly, neurological problems including synaptic loss, impaired neurogenesis and neuronal death, leading to dementia and cognitive decline are also observed in these patients. Since the brain utilizes glucose as a primary energy source, it is stipulated that dysregulated glucose levels may affect its homeostasis. In vivo studies have identified several pathophysiological mechanism in diabetic neurodegeneration, such as oxidative stress and neuroinflammation.
As the immune competent cells of the brain, microglia play a key role not only as the brain’s first line of defence against invasion, but they are also involved in synaptic pruning, neuronal development and interaction. Thus, abnormal microglia function is very detrimental for the brain homeostasis. In fact, it has been showed that diabetic animals have higher number of activated ameboid microglia and elevated inflammatory cytokines such as TNF-α. Nevertheless, the molecular mechanism behind this complex interaction remain poorly understood.
We aim to address this issue by studying human induced pluripotent stem cells (iPSC) derived microglia from healthy individuals and diabetic patients. We plan to analyse the effect of diabetic microglia on neurodegeneration by incorporating iPSC-derived microglia into brain organoids, perform in-depth metabolic analysis, and intervene the key metabolic dysfunction in diabetic microglia. Novel metabolic checkpoints in microglia metabolism will ameliorate neuroinflammation and lower the neurodegeneration in the diabetic patients.
Jarazo, J., et al., Parkinson’s Disease Phenotypes in Patient Neuronal Cultures and Brain Organoids Improved by 2-Hydroxypropyl-beta-Cyclodextrin Treatment. Mov Disord, 2021.
Smits, L.M., et al., Modeling Parkinson’s disease in midbrain-like organoids. NPJ Parkinsons Dis, 2019. 5: p. 5.
Monzel, A.S., et al., Derivation of Human Midbrain-Specific Organoids from Neuroepithelial Stem Cells. Stem Cell Reports, 2017. 8(5): p. 1144-1154.
Project 10: Torsten Bohn: Dietary factors, inflammation and oxidative stress related to metabolic syndrome – from molecular investigations to dietary patterns
Background: Metabolic syndrome (MetS) affects approx. 25% of adult people in Westernized countries, increasing the risk of morbidities such as diabetes or cardiovascular disease resulting in a huge socio-economic burden. MetS is characterized by inflammation and oxidative stress (OS) that impinge negatively on the immune system. Important factors linked to MetS are diet and epigenetics. Both are linked to OS and inflammation, and thus to the immune system.
Objective: To study the functional and molecular links between MetS, dietary components, inflammation, OS, and epigenetic regulation of gene expression.
Methods: In a first step, dietary patterns from the ORISCAV-LUX-2 study will be investigated for the interrelation of the dietary inflammatory index (DII) and systemic immune-inflammation (SII) index to MetS and epigenetic markers thereof. Untargeted plasma metabolomics, microRNA and RNA methylation profiles will be obtained from selected participants (<100) with and without MetS. Jointly analyzed using bioinformatics and interaction networks, these profiles will reveal diet- and MetS- related omics signatures. In a second step, the interrelation of selected dietary factors identified via ORISCAV, i.e. plant bioactives on their ability to suppress digestive enzymes (e.g. amylase) and pro-inflammatory and epigenetics pathways in selected cellular models relevant for inflammation/OS in the intestinal epithelium (Caco-2 cell based) and adipose tissue (e.g. 3T3-L1) will be studied.
Expected outcomes: This project will highlight the interplay of bioactive plant compounds, metabolic profiling, epigenetic signatures and the risk of MetS, with the final goal of identifying novel clinically applicable strategies to combat this major condition.
Menzel, A., et al., Common and Novel Markers for Measuring Inflammation and Oxidative Stress Ex Vivo in Research and Clinical Practice-Which to Use Regarding Disease Outcomes? Antioxidants (Basel), 2021. 10(3).
Ruiz-Castell, M., et al., Micronutrients and Markers of Oxidative Stress and Inflammation Related to Cardiometabolic Health: Results from the EHES-LUX Study. Nutrients, 2020. 13(1).
Samouda, H., et al., Relationship of oxidative stress to visceral adiposity in youth and role played by vitamin D. Pediatr Diabetes, 2020. 21(5): p. 758-765.
Project 11: Guy Fagherazzi: Deep digital and immuno-phenotyping of people with type 1 diabetes according to their metabolic and psychological stress levels for precision prevention of diabetes-related complications.
Background: Type 1 diabetes (T1D) is a frequent autoimmune disorder resulting from destruction of the β-cells in pancreatic islets1. Besides glycemic instability, mental burden, diabetes distress, fatigue, depressive symptoms are key risk factors for complications but little is known about their immunological impact.
Objectives: The project is divided into 3 objectives: 1) Deep digital phenotyping and clustering of people with T1D according to their levels of psychological and metabolic stress. 2) Deep immuno-phenotyping of people with T1D according to their levels of psychological and metabolic stress and study of the associations between immune and digital phenotypes. 3) Identification of clinically relevant deep digital and immuno-phenotyping clusters and study of their associations with diabetes-related microvascular complications and intermediate markers of cardiovascular health.
Material & Methods: The project is based on the SFDT1 study where up to 15,000 participants with T1D are currently being recruited in France. 1) Deep digital phenotyping will be performed on both data from continuous glucose monitoring devices and from e-patient reported outcomes of diabetes distress and anxiety in N=1500 participants. 2) Deep immuno-phenotyping will be based on frozen plasma blood samples (antibodies [ICA, AA,GAD, IA2/ICA512], cortisol, catecholamines, us CRP, IL-1ꞵ, IL-6, IL-17, TNF𝛂, MCP-1, anti-microbiota IgG, monocytes) in N=1000 participants. Machine learning and clustering techniques will be used to derive patterns of digital and immuno-phenotyping that are clinically relevant. Logistic regression models will also be employed to study the associations with the main diabetes-related complications.
Kiriella, D.A., et al., Unraveling the concepts of distress, burnout, and depression in type 1 diabetes: A scoping review. EClinicalMedicine, 2021. 40: p. 101118.
Ahne, A., et al., Insulin pricing and other major diabetes-related concerns in the USA: a study of 46 407 tweets between 2017 and 2019. BMJ Open Diabetes Res Care, 2020. 8(1).
Fagherazzi, G. and P. Ravaud, Digital diabetes: Perspectives for diabetes prevention, management and research. Diabetes Metab, 2019. 45(4): p. 322-329.
Project 12: Evan Williams: Systemic Effects of the Aging Microbiome on Metabolism and Health
The gut microbiome is composed of trillions of bacteria which can help with digestion and responses to environmental challenges, leading to numerous effects on health. This bacterial system interacts with the immune system, which can keep pathogenic bacteria in check. However, the immune system can also overreact leading to inflammation, reduction of beneficial bacteria, and autoimmune diseases like inflammatory bowel disease (IBD). In our project, we will continue our study of the BXD family of genetically diverse wild-type mice which naturally diverge in the development of metabolic diseases (e.g. obesity, diabetes, fatty liver disease). We have previously studied the impacts of high fat diet and exercise, and found some strains which are resistant to complex metabolic diseases in all cases, and others are nearly always susceptible. We have recently characterized the microbiome of young cohorts and observed major changes in the microbiome that associate with disease. We have recently finished collecting a metabolic study following the full natural lifespan of these strains, including intestinal tissue collection. We will examine the meta-genome and meta-transcriptome alongside the genome and transcriptome of the same animals’ intestinal tract. This will let us identify not only which microbes are associated with metabolic disease, but how, providing us with a mechanism for testing and characterizing how changing the gut microbiome can improve health. By understanding the time course for how differences in genetic background interact with dietary and lifestyle choices (i.e. exercise) to lead to metabolic disease in mice, we can translate these models to humans.
Williams EG, P.N., Roy S, Statzer C, Haverty J, Ingels J, Bohl C, Hasan M, Čuklina J, Bühlmann P, Zamboni N, Lu L, Ewald CY, Williams RW, Aebersold R, Multiomic profiling of the liver across diets and age in a diverse mouse population. Cell Systems, 2021.
Perez-Munoz, M.E., et al., Diet modulates cecum bacterial diversity and physiological phenotypes across the BXD mouse genetic reference population. PLoS One, 2019. 14(10): p. e0224100.
Williams, E.G., et al., Systems proteomics of liver mitochondria function. Science, 2016. 352(6291): p. aad0189.
Project 13: Mahesh Desai: Dietary fiber intervention in a human cohort study: links between the gut microbiome and the immune system
Over the past decades, intake of dietary fiber has substantially reduced in several human populations across the world. This decline in fiber consumption parallels an increase in prevalence of a multitude of autoimmune diseases. A possible link between dietary changes and the diseases could rest in the trillions of gut microbes that digest fibers and modulate the immune system. To better understand the functional link between fiber, the gut microbiome, and the host immune response, we are currently enrolling volunteers in a human cohort study. Using a 2×2 crossover study among healthy adults, 40 participants are randomly assigned to a low- or high-fiber dietary intervention and then, following a washout period to reverse any changes, switched to the other diet type. The proposed PhD project will involve deep immunophenotyping in blood using CyTOF to assess how short-term fiber deficiency exerts changes in the immune function. The analyses of the CyTOF data will enable to establish a possible link between microbial mucin foraging and immune responses in the face of fluctuating amounts of fiber intake. Based on the immune data, the next step of the project would include mechanistic studies in ex-germ-free mice transplanted with stool from select human donors to understand how intervention of specific types of dietary fibers alters the immune response via metabolism of the gut microbes. The proposed project would generate foundational knowledge to understand how various autoimmune diseases arise owing to the aberrations in the functional links between dietary fiber, the microbiota and the immune system.
Wolter, M., et al., Leveraging diet to engineer the gut microbiome. Nat Rev Gastroenterol Hepatol, 2021.
Neumann, M., et al., Deprivation of dietary fiber in specific-pathogen-free mice promotes susceptibility to the intestinal mucosal pathogen Citrobacter rodentium. Gut Microbes, 2021. 13(1): p. 1966263. Desai, M.S., et al., A Dietary Fiber-Deprived Gut Microbiota Degrades the Colonic Mucus Barrier and Enhances Pathogen Susceptibility. Cell, 2016. 167(5): p. 1339-1353 e21.
Project 14: Annette Kuehn: Integrative approach to identify drivers of acute immune responses in food allergy.
Supervisor: Dr Annette Kuehn, Co-supervisor: Dr Christiane Hilger.
Research keywords: food allergy, immune mechanisms
Collaborations: Centre Hospitalier de Luxembourg
Abstract: Food allergy is a complex pathology summarizing immune-mediated responses directed against specific foods. Predictive biomarkers of clinical key events – reaction phenotypes, disease prognosis and immunotherapy response – are evasive to date. The present study will base on a recently published work (doi: 10.1111/all.15408). Our aim is to address immune aspects underlying acute Th2-skewed inflammatory responses in order to provide insights in the pathophysiology of food allergy and inferring biomarkers being predictive for reaction patterns.
Klueber J, C.-M.F., Czolk R, Montamat G, Revets D, Konstantinou M, Cosma A, Hunewald O, Stahl Skov P, Ammerlaan W, Hilger C, Bindslev-Jensen C, Ollert M, Kuehn A, High-dimensional immune profiles correlate with phenotypes of peanut allergy during food-allergic reactions. under review.
Czolk, R., et al., IgE-Mediated Peanut Allergy: Current and Novel Predictive Biomarkers for Clinical Phenotypes Using Multi-Omics Approaches. Front Immunol, 2020. 11: p. 594350.
Kalic, T., et al., Patients Allergic to Fish Tolerate Ray Based on the Low Allergenicity of Its Parvalbumin. J Allergy Clin Immunol Pract, 2019. 7(2): p. 500-508 e11.
Project 15: Martyna Szpakowska: Unravelling the multidimensional regulation of the chemokine functions in health and disease with network-wide approaches
Chemokines are key regulators of the immune system. They play a central role in orchestrating the directional migration of leukocytes in immunosurveillance and immune responses Dysregulated chemokine signaling or skewed chemokine activity was linked to numerous diseases of the immune system such as inflammatory diseases and allergy.
To date 47 chemokines and 23 receptors have been identified in humans and form a highly intricate network (Fig. 1). The activity of chemokines and their receptors is proposed to be regulated on several levels including (I) tissue and cellular compartment expression, (II) receptor selectivity and promiscuity (III) posttranslational modifications (DDPIV or MMPs cleavage), (IV) synergism and antagonism through homo/heterodimerisation and (V) biased signalling (G protein vs arrestin signalling). However, the size and the complexity of the network have so far limited the possibility to precisely and systematically investigate these regulatory processes to obtain a more global understanding at their multiple levels, as well as their conservation and implication in healthy state and in diseases.
In this project, we propose to apply the NanoLux platform, a unique high-throughput system based on Nanoluciferase technologies recently established and validated in our team to investigate interactions, signalling events and functional networks for all known human receptors and chemokines. This unique tool offers for the first time the potential to explore and unravel the multidimensional regulation of the chemokine activity at the network-wide level and validate them using various models available at the DII and LIH and corroborate them with observations from patient samples.
Meyrath, M., et al., Systematic reassessment of chemokine-receptor pairings confirms CCL20 but not CXCL13 and extends the spectrum of ACKR4 agonists to CCL22. J Leukoc Biol, 2021. 109(2): p. 373-376.
Meyrath, M., et al., The atypical chemokine receptor ACKR3/CXCR7 is a broad-spectrum scavenger for opioid peptides. Nat Commun, 2020. 11(1): p. 3033.
Szpakowska, M., et al., Different contributions of chemokine N-terminal features attest to a different ligand binding mode and a bias towards activation of ACKR3/CXCR7 compared with CXCR4 and CXCR3. Br J Pharmacol, 2018. 175(9): p. 1419-1438.
Project 16: Jonathan Turner: NK cell senescence in adversity-divergent twins
Socioeconomic conditions have a significant impact on health and disease. In many cases, living in poor socioeconomic conditions is a major contributor to the cost of both acute as well as chronic care. Data from the previous FNR funded projects “EpiPath” and “MetCOEPs suggest that accelerated immunological ageing, the natural decline in immune functioning with age, may be key to understanding these health disparities. The psychosocial, socioeconomic and wider external environment influence immunosenescence and inflammaging, and have been associated with asthma, allergy, type 2 diabetes, mental disorders (depression, schizophrenia) as well as cardiovascular disease and hypertension. Poor life conditions are perhaps the most powerful driver of immuneageing. Previously we have shown how early-life adversity accelerates immunological ageing in adulthood with concurrent immunosenescence and altered numbers of circulating lymphocytes at baseline. The question remains as to whether this is limited to adversity in early-life, or whether it operates lifelong. One hundred adversity-discordant MZ twin pairs will undergo a detailed biological characterisation including a complete CyToF 30 member panel unbiased immune profiling and DNA methylation analyses in the recently funded project “ImmunoTwin”. While the ImmunoTwin project will focus on the overall immunophenotype, this PhD project will participate in ImmunoTwin data collection (CyToF), and then extract NK cell data, further exploring our recent data where psychosocial adversity reduced NK cell cytotoxicity, degranulation ability, and increased their senescence. Using Immunotwin material, scRNA-Seq will be performed on NK cells from a limited number of participants, and furthermore, epigenetic DNA methylation profiles will be obtained from selected populations.
Fernandes, S.B., et al., Unbiased Screening Identifies Functional Differences in NK Cells After Early Life Psychosocial Stress. Front Immunol, 2021. 12: p. 674532.
Elwenspoek, M.M.C., et al., Glucocorticoid receptor signaling in leukocytes after early life adversity. Dev Psychopathol, 2020. 32(3): p. 853-863.
Turner, J.D., et al., Twin Research in the Post-Genomic Era: Dissecting the Pathophysiological Effects of Adversity and the Social Environment. Int J Mol Sci, 2020. 21(9).
Project 17: Gunnar Dittmar: Glutathionylation as a negative regulator of the immune response
Glutathione (GSH) is the most important cellular antioxidant and a crucial regulator of T cell metabolism and function. Low levels of glutathione are connected to a low immunological response of T cells. Immune cells experiencing hypoxic conditions or reductive stress conditions can produce reactive oxygen species (ROS), which are counteracted by glutathione and other ROS scavengers. However, ROS scavenging is only one mechanism of how GSH ensures immune cell function. ROS conditions can promote glutathionylation of proteins, a post-translational modification of proteins on their Cysteine side chains. The impact of glutathionylation on T cell function and anti-tumor immunity has still to be elucidated. We hypothesize that glutathionylation plays an important role in the modulation of mitochondrial function. In this project, we will analyze the changes in the mitochondrial proteome of T and B cells using in vivo labeling techniques using a combination of cell organelle-specific labeling and SILAC labeling. This will allow us to monitor specific changes of the mitochondrial proteome and at the same time identify post-translational modification by glutathione and its derivatives Sulfhydryloxidations.
Ramberger, E., et al., PRISMA and BioID disclose a motifs-based interactome of the intrinsically disordered transcription factor C/EBPalpha. iScience, 2021. 24(6): p. 102686.
Dittmar, G. and M. Selbach, Deciphering the Ubiquitin Code. Mol Cell, 2017. 65(5): p. 779-780.
Schwanhausser, B., et al., Global quantification of mammalian gene expression control. Nature, 2011. 473(7347): p. 337-42.
Project 18: Markus Ollert: Regulation of the allergic airway Th2 response by redox metabolism
T helper-2 (Th2) cells are crucial in allergic inflammation. The complete transcriptional profile of Th2 cells has recently been elucidated by single-cell RNA sequencing (scRNA-seq) of T helper cells in the house dust mite model of allergic airway disease. The scRNA-Seq results pinpointed to a gene expression signature in Th2 cells that was highly enriched for Il1rl1 (ST2), Gata3, Il13, Il5, Ltb4r1, Plac8, and Pparg, all indicative of a pathologic Th2 cell phenotype. Other highly expressed genes not previously associated with Th2-cell immunity were found to be expressed in allergic airways, including Gclc, the gene for the catalytic subunit of glutamate cysteine ligase (GCL). GCL is catalyzing the rate-limiting step in glutathione (GSH) synthesis. Activated T cells control their intracellular reactive oxygen species particularly by GSH. To date, the role of GSH and of redox metabolism has not been addressed in a mechanistic approach during Th2 responses in IgE-mediated allergy. We will analyze conditional mutant mice lacking Gclc specifically in Th/Th2 cells using allergic asthma disease models developed by us. By targeting Gclc in T cells, Prof. Brenner’s group has demonstrated that antioxidation by GSH supports an environment essential for activation-induced metabolic reprogramming in T cells during antiviral and autoimmune responses. As key metabolic pathways (glucose and lipid metabolism) have also been demonstrated in Th2 cells during allergic inflammation, we expect a change in the phenotypic disease outcome during allergen re-exposure in an allergic asthma model in mice with Gclc deficiency in Th/Th2 cells.
Mak, T.W., et al., Glutathione Primes T Cell Metabolism for Inflammation. Immunity, 2017. 46(4): p. 675-689.
Leonard, C., et al., Comprehensive mapping of immune tolerance yields a regulatory TNF receptor 2 signature in a murine model of successful Fel d 1-specific immunotherapy using high-dose CpG adjuvant. Allergy, 2021. 76(7): p. 2153-2165.
Golebski, K., et al., Induction of IL-10-producing type 2 innate lymphoid cells by allergen immunotherapy is associated with clinical response. Immunity, 2021. 54(2): p. 291-307 e7.
Project 19: Michel Mittelbronn: Impact of the interplay between microglia, astrocytes and infiltrating immune cells in neuroinflammatory mechanisms in Alzheimer’s disease.
Alzheimer’s disease (AD), the prevalent age-associated neurodegenerative disease, is associated with neuroinflammation and impaired immunity. Microglia, the brain resident immune cells, are often looked at as responsible for this pathological cascade. However, growing evidence shows the contribution of peripheral immune cells and astrocytes to the brain immune responses in AD. The astrocytes, mainly known for their metabolic support to neurons, can secrete a plethora of pro-inflammatory cytokines under reactive profiles and alter the responses of surrounding microglia. Furthermore, CD8+ T cells have been shown to infiltrate parenchyma in neurodegeneration areas and could derail inflammation.
Deciphering microglia interplays with astrocytes and T cells will unveil new facets of neuroinflammation in AD and potentially open new therapeutic strategies to alleviate the progression of the disease.
We propose investigating their interactions using a translational approach based on co-cultures of human cells, on single nuclei-RNAseq analysis and high-resolution microscopy of AD post-mortem tissue. Briefly, we will use human cells, isolated or induced, to study the impact of cytotoxic lymphocytes and reactive astrocytes (chemically induced) on the physiology of microglia in mono or 3D co-culture models. We will use a complete set of molecular screening (methylation profiling, PCR, WB, secretome, and metabolic signatures), time-lapse microscopy and super-resolution shadow imaging (SUSHI) to characterize their phenotypic changes and cellular interactions.
In parallel, we will analyze the transcriptome of immune and brain cells in vulnerable regions by single-nuclei RNAseq (10x) in our collection of frozen AD brain samples. We will decode regional immune signatures and characterize respective local cellular relationships using neuropathology, confocal microscopy and correlative light electron microscopy.
Heurtaux, T., et al., Apomorphine Reduces A53T alpha-Synuclein-Induced Microglial Reactivity Through Activation of NRF2 Signalling Pathway. Cell Mol Neurobiol, 2021.
Uriarte Huarte, O., et al., Single-Cell Transcriptomics and In Situ Morphological Analyses Reveal Microglia Heterogeneity Across the Nigrostriatal Pathway. Front Immunol, 2021. 12: p. 639613.
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For any question related to the NextImmune2 DTU, please contact :
Prof Dirk Brenner
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For any question related to the NextImmune2 DTU, please contact :
Prof Dirk Brenner
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