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The Transregional Collaborative Research Center “Perinatal Development of Immune Cell Topology (PILOT)” is a new research consortium examining the development of the immune system around birth.

PILOT aims to break new ground by exploring mechanisms that determine perinatal differentiation of immune cells and their cellular environment. In particular, PILOT will dissect how preprogrammed developmental traits and perinatal exogenous cues integrate to steer immune cell differentiation, establish immune homeostasis and provide efficient immunity to infections. PILOT focuses on analyzing preprogrammed development, the impact of the birth transition and the influence of postnatal cues on immune cell and tissue development. We will study particular subanatomical niches, where structures with discrete functions meet, such as barrier tissues of intestine, lung and skin, and protected sites including the placenta.

Overall, identification and modification of key parameters determining immunity around birth promises unique insights into how the architecture of cellular immunity evolves in adaptation between host and environment on the global level, and microanatomically in the tissue. This will lay the foundation for PILOT’s ultimate goal: steering immunity for a better start and for long-term health.

PILOT brings together scientists from several institutions across Germany:

The new consortium will be led by PILOT’s director, Philipp Henneke (Freiburg), together with deputy director Markus Sperandio (LMU Munich) and Steering Committee members Katrin Kierdorf (Freiburg) and Mathias Hornef (Technical University Aachen). PILOT will be funded by the German Research Foundation with a total of around 12 million Euros from January 1, 2023 for an initial period of four years.

Project summaries

M. Hornef observed that early-life infection with the human enteropathogen Salmonella impacts on the fetal-neonatal transition of the intestinal epithelium. Early Salmonella infection may therefore influence nutrient digestion, substrate absorption, energy metabolism and microbiota establishment, as well as antimicrobial host defense activation. Based on substantial preliminary and published data, A01 explores molecular mechanisms of these effects and the resulting influence of altered substrate availability on mucosal antimicrobial properties. A01 brings longstanding expertise on mucosal immune development and intestinal infections in neonatal mice, with benefits for many groups working on microbial challenges in barrier tissues.

Project leader: Mathias Hornef

Henneke and Z. Ruzsics recently discovered that cytomegalovirus (CMV) remodels the identity of fully differentiated alveolar macrophages (Mφ). A02 combines this knowledge with insights into how chronic infections manipulate Mφ progenitors to explore how perinatal CMV infections impact on innate cellular barrier immunity. A particular focus will be renewal and function of resident lung Mφ subsets, and thus on immunity to bacterial pneumonia later in life. Several groups in the consortium will profit from the broad expertise in viral and bacterial neonatal infections, and myeloid cell development as provided by A02.

Project leaders: Philipp Henneke and Zsolt Ruzsics

The project leaders previously found that S100-alarmins are endogenous factors that tune systemic and gut immunity after birth, thereby ensuring immune adaptation to the environment. A03 will explore S100A8/A9 in the perinatal development of lung and airway immunity, with a focus on neonatal and long-term programming of epithelial cells and cross-talk with professional immune cells, platelets and the vascular system. A03 will also elucidate the cellular source of S100A8/A9 in the amniotic fluid by investigating non-immune cells in the lung. A03 contributes elaborate tools for steering immunity and analyzing its regulation in neonatal mice and newborn infants with an explicit translational focus.

Project leaders: Dorothee Viemann and Konstantin Stark

This project will explore the hypothesis that postnatal development of γδ T cells and Langerhans cells (LC) in epidermis and oral mucosa is highly dependent on the dynamic interplay of these two resident immune cells within the perinatal time window. The project aims to define the differentiation dynamics and molecular crosstalk between γδ T cells and LC in two distinct tissue niches, and will explore the role of microbial colonization during γδ T cell/LC differentiation and adaptation. This joint project brings expertise on γδ T cell development, advanced single cell sequencing approaches, and myeloid cell development to PILOT.

Project leaders: Katrin Kierdorf and Sagar

A05 will investigate the long-lasting consequences of early-life influenza A virus (IAV) infections in terms of adaptation of the lung microenvironment and susceptibility to secondary bacterial infections later in life. In particular, the project will examine how IAV infections alter lung-resident immune cell populations. These alterations may contribute to the formation of tissue-resident memory T cell niches and affect the response to secondary pneumococcal infections in adulthood. A05 offers sophisticated single-cell analytics as well as lung infection models to the consortium.

Project leaders: Dunja Bruder and Jochen Hühn

A06 will explore the co-development of the neonatal microbiota and intestinal Mφ, focusing on metabolic programming and epigenetic imprinting in the integration of potentially highly pathogenic mucosal colonizers, in particular streptococci, into the host-adapted microbiota. Molecular and cellular mechanisms underlying co-evolution of a stable intestinal host-microbe interface will be explored. A06 commands specific knowledge in perinatal bacterial colonization and infection models and microbiota analysis, which will be instrumental for other PILOT projects studying the developing host-microbe interface.

Project leaders: Daniel Erny, Tom Clavel and Philipp Henneke

A07 will study the impact of the microbiota on the neonatal vaccine-induced germinal center reaction. The proposal is based on the investigators’ fundamental discoveries that “wildling” mouse microbiota tunes systemic immunity in a way that better reflects human immune responses than microbiota found under specific-pathogen-free conditions. The project explores the impact of wild microbiota 1) on the capacity of dendritic cells from young mice to mediate T cell help in influenza infections and 2) on vaccination. The groups have unique knowhow in modulating and analyzing the host-microbe interface, in particular at the level of a highly complex microbiota, which will be extremely useful for many projects in PILOT.

Project leaders: Michele Proietti and Stephan Rosshart

Hilgendorff and H. Schiller combine complementary expertise on human and mouse neonatal lung development and on transcriptomics in lung cells to study consequences of oxygen therapy and of mechanical forces on the interaction of lung immune and non-immune cells. The project explores mechanisms underlying innate immune cell differentiation in chronic lung disease of preterm infants. A08 will use an existing cohort of preterm infants including longitudinal biomaterial, and a new small prospective cohort. The project offers PILOT models for human “fetal development” ex utero and under physical stress, as well as expertise in multidimensional cellular analysis.

Project leaders: Anne Hilgendorff and Herbert Schiller

B01 will expand M. Prinz’s work on myeloid cell development starting in embryonic life by delineating patterns of ontogeny, underlying transcriptional programs and molecular signals driving the perinatal development of parenchymal (pMφ) as opposed to perivascular Mφ (periMφ). The project focuses on tissues that are largely protected from direct microbial contact (brain, heart, kidney) and exploits novel fate mapping systems, single-cell profiling and cell-specific mutants to define pre- to postnatal check points, tissue-specific niches and cues that modify the fate and function of pMφ and periMφ. PILOT will benefit from M. Prinz’s groundbreaking discoveries and expertise in myeloid fate mapping and cell lineage tracing.

Project leader: Marco Prinz

Sperandio and R. Immler will exploit their methodological knowledge of intravital imaging and leukocyte recruitment in the fetus to investigate the mechanistic role of the peptide Preimplantation Factor (PIF) in the regulation of maternal and fetal immune cells. The project will evaluate the impact of PIF on fetal immune cell programming and study the regulation of PIF itself during pregnancy. B02 provides unique knowledge in fetal imaging, leukocyte trafficking and neutrophil physiology to PILOT.

Project leaders: Markus Sperandio and Roland Immler

B03 will combine lineage tracing of highly-dedicated dermal Mφ with proficiency in single cell epigenomics. The project explores factors driving perinatal development of dermal Mφ diversity with a focus on 1) identification of novel Mφ niches in the dermis, 2) perinatal competition between fetal and bone-marrow-derived cells for immunological niches in the dermis, 3) limits of and cues for dermal Mφ subset plasticity. Single-cell transcriptomics and epigenomics, fate mapping, and high-resolution tissue imaging will be employed. Including B03 will enable the consortium to profit from expert knowledge in these technologies.

Project leaders: Julia Kolter and Sebastian Preißl

B04 concentrates on fibroblasts and their role in immune cell maturation and function. This proposed work is based on seminal discoveries on fetal fibroblast diversity and function, in particular with respect to scarless wound closure in the fetus, and the role of heterocellular interactions between fibroblasts and neutrophils in scar formation. The impact of fibroblast-immune cell crosstalk on shaping perinatal skin immunity will be explored in terms of fibroblast and connective tissue niche development and adaptation, with a particular focus on the dynamics in stress/injury (in vivo fetal/perinatal skin wound models). These models will be extremely useful for other PILOT groups studying heterocellular interactions in developing tissues.

Project leader: Yuval Rinkevich

Schraml-Schotta tackles the question of whether maternal inflammation shapes the dendritic cell (DC) compartment in the offspring via inflammatory cytokines. The project investigates the impact of prenatal inflammation on the origin, phenotype and function of the neonatal DC compartment. The time course of DC responsiveness to maternal inflammation will be characterized using fate mapping. Fate mapping, functional analyses and transcriptional profiling of neonatal immune cells are within the core expertise of B05.

Project leader: Barbara Schraml-Schotta

B06 will investigate the role of cis-regulatory genetic variants on blood protein expression during perinatal immune cell development in human neonates, by exploiting the Munich Preterm and Term clinical (MUNICH-PreTCl) birth cohort. Next to mass spectrometry-based blood proteomes, genome-wide genotypes of single nucleotide polymorphisms will be generated for proteomic in silico cell type deconvolution of the human neonatal immune system with a focus on neutrophils. This complex basic project with high translational potential will make use of the applicants’ expertise in cell type-interaction expression quantitative trait loci mapping, which will substantially aid other PIs in PILOT in their translational approaches.

Project leaders: Sarah Kim-Hellmuth and Claudia Nussbaum

B07 will elucidate how circadian rhythms in myeloid cell function and trafficking are established in the perinatal period. The project will define the time window during which these rhythms develop and explore their relevance in disease. The project is based on previous discoveries of the group concerning steering of leukocyte functions by circadian rhythms. In particular, mechanisms that govern these rhythms in the fetus just before birth and in the neonate will be studied. Finally, the relevance of these rhythms will be explored in a neonatal bacterial sepsis model. B07 contributes outstanding knowledge on the chronobiology of leukocytes and intravital imaging to PILOT.

Project leaders: Christoph Scheiermann and Markus Sperandio

B09 will analyze how maternal hyperlipidemia affects embryonic Mφ, which are at the core of the C. Schulz’s research interests. Tools include temporal control of metabolic disease activity during pregnancy with low density lipoprotein receptor anti-sense oligonucleotides, cross fostering experiments, and long-term phenotyping of prenatally exposed mice. Furthermore, human placental pathology will be studied with a focus on embryo-derived Hofbauer Mφ and maternal decidua Mφ. PILOT will benefit from C. Schulz’s widely-recognized proficiency in tracing Mφ development from the embryo to postnatal life.

Project leader: Christian Schulz

The INF project will develop a technical platform and processes for Research Data Management (RDM), tailored to the needs of PILOT. Annotation of research data with metadata will make data Findable, Accessible, Interoperable, and Reusable, thus FAIR. The INF project will analyze data workflows jointly with PILOT project leaders and provide custom solutions for facilitating metadata annotation, based on established terminologies and ontologies. The INF project will also help to set up and maintain a Data Use And Access Committee to support PILOT in making data available externally, and to organize central long-term data storage and access. INF brings crucial expertise on RDM in large consortia to PILOT.

Project leader: Harald Binder

The Integrated Research Training Group (IRTG) “CoPILOT” offers natural science and medical doctoral (MD) candidates distributed over the consortium’s various geographical locations a structured training program to address unique theoretical and methodological aspects of perinatal immune cell development. CoPILOT will provide optimal support to doctoral candidates to pursue advanced training in a cutting-edge scientific environment, forming a new generation of scientific leaders in the area of perinatal immunology. Simultaneously, CoPILOT members will embody the bottom-up scientific network interconnecting the geographically distant PILOT groups.

Project leaders: Markus Sperandio and Katrin Kierdorf

Börries and C. Marr (Z01) will provide standardized workflows for the computational analysis of biomedical data from mice and humans to quantify and model perinatal immune development within the consortium. The project will develop and apply methods for the statistical analysis and integration of heterogeneous high-throughput and multi-omics data, in particular transcriptome, epigenome, proteome and imaging data with single-cell resolution. Special efforts will be made in the integration of multidimensional data from diverse sources, including the use of artificial intelligence and machine learning in selected PILOT projects. Project leaders will support PILOT researchers in understanding, running and adapting basic omics and image analysis workflows using existing tools and in-house algorithms.

Project leaders: Melanie Börries and Carsten Marr

The Z02 project will be responsible for all aspects of coordination and administration of PILOT, including supporting the constituent bodies; monitoring project progress and evaluating achievement of milestones; supporting cross-project and cross-site scientific activities; managing joint training activities (other than those organized via the IRTG); planning and organizing scientific meetings and annual CRC TRR retreats; internal CRC TRR communication; public relations work, including setting up and maintaining a website and assisting with press releases in liaison with relevant university press offices; and administration of general finances.

Project leader: Philipp Henneke