Biology subjects

Foerster, R.

Publications and source records attributed to Foerster, R..

7 recordsLinked to original sources

bioRxiv2024

Integrative deep immune profiling of the elderly reveals systems-level signatures of aging, sex, smoking, and clinical traits

Elderly individuals have higher disease susceptibility and lower vaccine responsiveness, highlighting the need to better comprehend the aging immune system and its clinical associations. Here we conducted a deep immune profiling study of 550 elderly individuals (61-94 years) and 100 young adults (22-38 years). Utilizing high-dimensional spectral flow cytometry to identify 97 immune cell populations and 48-plex cytokine profiling, we detailed intricate age-and sex-related changes in the elderly immune system at an unprecedented depth. Synthesizing information from clinical, laboratory, and immunological data through an integrative multi-block analysis, we reveal overarching systems-level signatures of aging, such as increased concentrations of specific cytokines and frequencies of defined innate and adaptive immune cell subpopulations. Extending this approach, we identified unique immune signatures of smoking, obesity, and several diseases including osteoporosis, heart failure and gout. Our systems biology approach enables to uncover new relationships between clinical characteristics and immunological traits.

immunology↗

bioRxiv2024

Protective function of ex vivo expanded CD8 T cells in a mouse model of adoptive therapy for cytomegalovirus infection depends on integrin beta 1 but not CXCR3, CTLA4, or PD-1 expression

The adoptive transfer of virus-specific T cells (VSTs) represents a therapeutic option for viral infection treatment in immunocompromised patients. Before administration, ex vivo culture enables VST expansion. However, it is unclear how ex vivo expansion affects the circulation, homing, and intra-tissue migration of administered VSTs. We established a model of VST immunotherapy of acute cytomegalovirus infection using adoptive transfer of ex vivo expanded OT-I CD8 T cells (recognizing SIINFEKL peptide) into Rag2-/- mice infected with murine cytomegalovirus (MCMV) encoding for the SIINFEKL peptide. Ex vivo expansion induced an effector T cell phenotype and affected the expression of integrins and chemokine receptors. CRISPR/Cas9-mediated gene deletions enabled us to address the role of selected genes in the homing of VSTs following intravenous administration. We found that deletion of Itgb1, encoding for integrin beta 1, prevented OT-I cells from entering infected organs and drastically reduced their number in blood, suggesting that adoptively transferred VSTs primarily expand in the infected tissues. In contrast, Cxcr3-/- OT-I cells provided equal protection as their Cxcr3+/+ counterparts, indicating that this chemokine receptor does not contribute to VST entry into infected organs. Further, Pdcd1 and Ctla4 deletion did not impair the transferred OT-I cells ability to protect mice from MCMV, arguing against quick exhaustion of VSTs with an effector T cell phenotype. Together, these data indicate that ex vivo expansion affects migration and activation properties of VSTs and suggest that future clinical evaluation of adoptive T cell therapy efficacy should include homing molecule expression assessment.

immunology↗

bioRxiv2023

Adult thymus-derived cMaf+ RORγt+ γδ T cells lack Scart2 chromatin accessibility and do not reach periphery

T cell receptor (TCR) V{gamma}4+ expressing {gamma}{delta} T cells can be divided into IFN-{gamma} and IL-17-producing effector T cell subsets. A bias towards {gamma}{delta}17 effector fate decisions is observed during early ontogeny. In contrast, the existence of V{gamma}4+ {gamma}{delta}17 cells derived from adult thymus is still controversial. In the present work, we used a mouse model where T cells are exclusive generated within an adult thymus. Additionally, we employed single-cell chromatin state analysis from thymocytes of normal mice. A small, but considerable population of immature Cd24+ Gzma+ V{gamma}4 cells was found that exhibit molecular programs of {gamma}{delta}17 cells. These adult thymus-derived immature Cd24a+ cMaf+ V{gamma}4 cells secrete small amounts of IL-17A and IL-17F. Interestingly, do not reach the periphery under steady-state conditions. Furthermore, de novo generated {gamma}{delta}17-like cells from adult thymus lack transcriptional activity of the Scart2 encoding gene, suggesting that Scart2 is a distinct trait of fetal {gamma}{delta} T cell precursors. Together, this study provides valuable insights into developmental traits of V{gamma}4 cells during adulthood and raises the question on signals suppressing the full maturation and/or thymic export of {gamma}{delta}17-like cells within the adult thymus. HighlightsO_LITranscriptional and epigenetic profiling identifies developmental plasticity of Gzma+ Cd24a+ V{gamma}4 cells in adult thymus. C_LIO_LIThymic c-Maf+ and ROR{gamma}t+ V{gamma}4 T cells can be generated during adulthood, but do not reach the periphery under steady-state conditions. C_LIO_LIInnate CD44highCD45RBneg {gamma}{delta}17 cells are completely absent upon induction of T cell development during adulthood. C_LIO_LIScart2 expression might be a key molecule to track developmental traits of fetal-derived {gamma}{delta}17 cell precursors. C_LI

immunology↗

bioRxiv2022

MHC class Ia molecules facilitate MCK2-dependent MCMV infection of macrophages and virus dissemination to the salivary gland

Murine cytomegalovirus (MCMV) infection of macrophages relies on MCMV-encoded chemokine 2 (MCK2) through one or more unknown cellular receptors while infection of fibroblast occurs independent of MCK2 and is mediated by cell-expressed neuropilin 1. Applying a CRISPR screen, we now identified that the MHC-Ia/Beta-2-microglobulin (B2m) complex serves as an entry port for MCK2-mediated infection of macrophages. Further analyses revealed that MCK2-dependent infection requires expression of the MHC-Ia haplotypes H-2b and H-2d but not H-2k. The importance of the MCK2-MHC-I-pathway for primary infection and viral dissemination was highlighted by experiments with B2m-deficient mice, which lack surface expression of MHC-I molecules. In those mice, intranasally administered MCK2-proficient MCMV could not infect alveolar macrophages and subsequently failed to disseminate into the salivary glands. The identified molecular pathway used by MCMV to infect lung resident macrophages provides essential knowledge for understanding cytomegalovirus-induced pathogenesis, tissue targeting, and virus dissemination.

immunology↗

bioRxiv2021

Immunogenicity and efficacy of the COVID-19 candidate vector vaccine MVA SARS 2 S in preclinical vaccination

The severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) has emerged as the infectious agent causing the pandemic coronavirus disease 2019 (COVID-19) with dramatic consequences for global human health and economics. Previously, we reached clinical evaluation with our vector vaccine based on vaccinia virus MVA against the Middle East respiratory syndrome coronavirus (MERS-CoV), which causes an infection in humans similar to SARS and COVID-19. Here, we describe the construction and preclinical characterization of a recombinant MVA expressing full-length SARS-CoV-2 spike (S) protein (MVA-SARS-2-S). Genetic stability and growth characteristics of MVA-SARS-2-S, plus its robust synthesis of S antigen, make it a suitable candidate vaccine for industrial scale production. Vaccinated mice produced S antigen-specific CD8+ T cells and serum antibodies binding to S glycoprotein that neutralized SARS-CoV-2. Prime-boost vaccination with MVA-SARS-2-S protected mice sensitized with a human ACE2-expressing adenovirus from SARS-CoV-2 infection. MVA-SARS-2-S is currently being investigated in a phase I clinical trial as aspirant for developing a safe and efficacious vaccine against COVID-19. Significance StatementThe highly attenuated vaccinia virus MVA is licensed as smallpox vaccine, and as vector it is a component of the approved Adenovirus-MVA-based prime-boost vaccine against Ebola virus disease. Here we provide results from testing the COVID-19 candidate vaccine MVA-SARS-2-S, a poxvirus-based vector vaccine that proceeded to clinical evaluation. When administered by intramuscular inoculation, MVA-SARS-2-S expresses and safely delivers the full-length SARS-CoV-2 spike (S) protein, inducing balanced SARS-CoV-2-specific cellular and humoral immunity, and protective efficacy in vaccinated mice. Substantial clinical experience has already been gained with MVA vectors using homologous and heterologous prime-boost applications, including the immunization of children and immunocompromised individuals. Thus, MVA-SARS-2-S represents an important resource for developing further optimized COVID-19 vaccines.

microbiology↗

bioRxiv2020

A fetal wave of human type-3 γδ T cells with restricted TCR diversity persists into adulthood

Accumulating evidence suggests that the human embryonic thymus produces distinct waves of innate effector {gamma}{delta} T cells. However, it is unclear whether this process comprises a dedicated subset of IL-17-producing {gamma}{delta} T ({gamma}{delta}T17) cells, like reported in mice. Here we present a novel protocol for high-throughput paired {gamma}{delta} TCR-sequencing, which in combination with single-cell RNA-sequencing revealed a high heterogeneity of effector {gamma}{delta} T cell clusters. While immature {gamma}{delta} T cell clusters displayed mixed and diverse TCR, effector cell types in neonatal and adult blood segregated according to {gamma}{delta}TCR usage. In adult samples, mature V{delta}1+ T cells segregated into exhausted PD-1hi and active PD-1low clusters. Among V{gamma}9V{delta}2+ T cell subsets, we identified distinct PLZF-positive effector {gamma}{delta} T cell clusters with innate type-1 and type-3 T cell signatures that were already detectable in a public dataset of early embryonic thymus organogenesis. Together, this suggests that functionally distinct waves of human innate effector {gamma}{delta} T cells including CCR6+ {gamma}{delta}T17 cells develop in the early fetal thymus and persist into adulthood.

immunology↗

bioRxiv2018

Successful optimization of reconstruction parameters in structured illumination microscopy - a practical guide

The impact of the different reconstruction parameters in super-resolution structured illumination microscopy (SIM) onto artifacts is carefully analyzed. They comprise the Wiener filter parameter, an apodization function, zero-frequency suppression and modifications of the optical transfer function. A detailed investigation of the reconstructed image spectrum is concluded to be suitable for identifying artifacts. For this purpose, two samples, an artificial test slide and a more realistic biological system, were used to characterize the artifact classes and their correlation with the image spectra as well as the reconstruction parameters. In addition, a guideline for efficient parameter optimization is suggested and the implementation of the parameters in selected up-to-date processing packages (proprietary and open-source) is depicted.

bioinformatics↗