Biology subjects

Pressler, M.

Publications and source records attributed to Pressler, M..

7 recordsLinked to original sources

bioRxiv2026

A Donor T-Cell Receptor Structural Signature Determines Alloreactive Potential and Predicts Acute Graft-Versus-Host Disease

Acute graft-versus-host disease (GVHD) remains a lethal barrier to successful allogeneic hematopoietic cell transplantation, yet pre-transplant donor selection entirely ignores hypervariable T-cell receptor (TCR) architecture. Here, by characterizing over 64,000 alloreactive clonotypes, we demonstrate that human alloreactivity is dictated by a constrained, predictable baseline structural signature. Pathogenic, tissue-infiltrating alloreactive T cells exhibit significantly shortened CDR3{beta} regions, altered antigen-facing biophysical features, biased VJ gene usage and extensive inter-donor sharing originating from public anti-pathogen memory reservoirs. These potent clones natively cluster within the high-frequency fraction of the unstimulated baseline donor repertoire. We introduce R50, an assay-independent metric quantifying this clonal dominance, which independently predicted a six-fold increased risk of acute GVHD in a cross-institutional cohort. This scalable in silico platform shifts pre-transplant risk stratification from HLA typing and demographic surrogates to precision immune-receptor modeling.

immunology↗

bioRxiv2025

CDK4/6 inhibition induces a DNA damage-independent senescence-associated secretory phenotype driven by delayed activation of NF-κB

Cellular senescence consists of regulated cell phenotypes associated with permanent exit from the cell cycle in response to stressors such as genomic instability. The consequences of senescence go beyond individual cells due to the senescence associated secretory phenotype (SASP), which can induce inflammation in neighboring cells. Some cancers respond to CDK4/6 inhibitors (CDK4/6i)--a family of targeted therapies that inhibit proliferation--with a senescence-like phenotype in the absence of DNA damage. We asked how the SASP and the transcriptional regulatory profile triggered by CDK4/6i-driven arrest compares to the canonical NF-{kappa}B-regulated SASP triggered by DNA damage. We profiled the temporal dynamics of transcriptional regulation in response to the CDK4/6i, palbociclib, and the DNA damaging agent, doxorubicin. We found that, although upregulation of NF-{kappa}B driven-SASP genes is shared across both drugs, it is delayed in CDK4/6i. This coincides with slower enhancer activation and epigenetic changes. Interestingly, ATM/ATR inhibition does not affect CDK4/6i-induced NF-{kappa}B nuclear localization, pointing to an alternative mechanism driving NF-{kappa}B activity in the absence of DNA damage. Inhibiting NF-{kappa}B suppresses the expression of shared SASP genes without reversing stable arrest. This points to SASP manipulation as a potential therapeutic strategy, and resolves an ongoing controversy about the nature of cell cycle arrest-driven SASP.

cancer biology↗

bioRxiv2025

Spatiotemporal Single-Cell Analysis Reveals T Cell Clonal Dynamics and Phenotypic Plasticity in Human Graft-versus-Host Disease

Allogeneic hematopoietic cell transplantation (alloHCT) is curative for various hematologic diseases but often leads to acute graft-versus-host disease (GVHD), a potentially life-threatening complication. We leverage GVHD as a uniquely tractable disease model to dissect complex T-cell-mediated pathology in 27 alloHCT recipients. We integrate pre-transplant identification of alloreactive T-cells with longitudinal tracking across blood and gut, using mixed lymphocyte reaction-based clonal "fingerprinting", TCR clonotyping, single-cell RNA/TCR sequencing, and spatial transcriptomics. Using DecompTCR, a novel computational tool for longitudinal TCR analysis, we uncover clonal expansion programs linked to GVHD severity and TCR features. Multi-omics profiling of gut biopsies reveals enrichment and clonal expansion of CD8 effector and ZNF683(Hobit) resident memory T-cells, cytolytic remodeling of regulatory and unconventional T-cells, and localization of CD8 effector T-cells near intestinal stem cells in crypt loss regions. This framework defines dynamic immune circuit rewiring and phenotypic plasticity with implications for biomarkers and therapies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=198 SRC="FIGDIR/small/655962v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@178b77dorg.highwire.dtl.DTLVardef@569226org.highwire.dtl.DTLVardef@1951281org.highwire.dtl.DTLVardef@1f1e046_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIPersistent expansion of diverse alloreactive T cell clones is a hallmark of severe GVHD C_LIO_LIDecompTCR reveals dynamic clonal expansion programs linked to GVHD severity and clinical outcome C_LIO_LICD8+ T cell clones exhibit phenotypic plasticity in vivo across intestinal tissue compartments in GVHD C_LIO_LIHigh-resolution spatial profiling shows CD8+ effector T cells localize near intestinal stem cell niches and drive epithelial injury in GVHD C_LI

systems biology↗

bioRxiv2024

Modeling and Correction of Protein Conformational Disease in iPSC-derived Neurons through Personalized Base Editing

AbstractAltered protein conformation can cause incurable neurodegenerative disorders. Mutations in SERPINI1, the gene encoding neuroserpin, can alter protein conformation resulting in cytotoxic aggregation leading to neuronal death. Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a rare autosomal dominant progressive myoclonic epilepsy that progresses to dementia and premature death. We developed HEK293T and induced pluripotent stem cell (iPSC) models of FENIB, harboring a patient-specific pathogenic SERPINI1 variant or stably overexpressing mutant neuroserpin fused to GFP (MUT NS-GFP). Here, we utilized a personalized adenine base editor (ABE)-mediated approach to correct the pathogenic variant efficiently and precisely to restore neuronal dendritic morphology. ABE-treated MUT NS-GFP cells demonstrated reduced inclusion size and number. Using an inducible MUT NS-GFP neuron system, we identified early prevention of toxic protein expression allowed aggregate clearance, while late prevention halted further aggregation. To address several challenges for clinical applications of gene correction, we developed a neuron-specific engineered virus-like particle to optimize neuronal ABE delivery, resulting in higher correction efficiency. Our findings provide a targeted strategy which may treat FENIB and potentially other neurodegenerative diseases due to altered protein conformation such as Alzheimers and Huntingtons diseases.

molecular biology↗

bioRxiv2022

Complex changes in serum protein levels upon recovery from SARS-CoV2 infection

The COVID-19 pandemic, triggered by severe acute respiratory syndrome coronavirus 2, has affected millions of people worldwide. Much research has been dedicated to our understanding of COVID-19 disease heterogeneity and severity, but less is known about recovery associated changes. To address this gap in knowledge, we quantified the proteome from serum samples from 29 COVID-19 convalescents and 29 age-, race-, and sex-matched healthy controls. Samples were acquired within the first months of the pandemic. Many proteins from pathways known to change during acute COVID-19 illness, such as from the complement cascade, coagulation system, inflammation and adaptive immune system, had returned to levels seen in healthy controls. In comparison, we identified 22 and 15 proteins with significantly elevated and lowered levels, respectively, amongst COVID-19 convalescents compared to healthy controls. Some of the changes were similar to those observed for the acute phase of the disease, i.e. elevated levels of proteins from hemolysis, the adaptive immune systems, and inflammation. In contrast, some alterations opposed those in the acute phase, e.g. elevated levels of CETP and APOA1 which function in lipid/cholesterol metabolism, and decreased levels of proteins from the complement cascade (e.g. C1R, C1S, and VWF), the coagulation system (e.g. THBS1 and VWF), and the regulation of the actin cytoskeleton (e.g. PFN1 and CFL1) amongst COVID-19 convalescents. We speculate that some of these shifts might originate from a transient decrease in platelet counts upon recovery from the disease. Finally, we observed race-specific changes, e.g. with respect to immunoglobulins and proteins related to cholesterol metabolism.

immunology↗

bioRxiv2022

Proteomic signatures of the serological response to flu vaccination in a large human cohort study

The serological response to the influenza virus vaccine is highly heterogeneous for reasons that are not entirely clear. While the impact of demographic factors such as age, body mass index (BMI), sex, prior vaccination and titer levels are known to impact seroconversion, they only explain a fraction of the response. To identify signatures of the vaccine response, we quantified 273 proteins from serum samples of 160 flu vaccine recipients (2019-2020 season). We found that levels of proteins functioning in cholesterol transport were positively associated with seroconversion, likely linking to the known impact of BMI. When adjusting seroconversion for the demographic factors, we identified additional, unexpected signatures: proteins regulating actin cytoskeleton dynamics were significantly elevated in participants with high adjusted seroconversion. Viral strain specific analysis showed that this trend was largely driven by the H3N2 strain. Further, we identified complex associations between adjusted seroconversion and other factors: levels of proteins of the complement system associated positively with adjusted seroconversion in younger participants, while they were associated negatively in the older population. We observed the opposite trends for proteins of high density lipoprotein remodeling, transcription, and hemostasis. In sum, careful integrative modeling can extract new signatures of seroconversion from highly variable data that suggest links between the humoral response as well as immune cell communication and migration.

immunology↗

bioRxiv2021

Regulatory start-stop elements in 5' untranslated regions pervasively modulate translation

Sequence elements within the 5 untranslated region (UTR) of eukaryotic genes, e.g. upstream open reading frames (uORFs), control translation of eukaryotic genes. We describe an element consisting of a start codon immediately followed by a stop codon which is distinct from uORFs in the lack of an elongation step. Start-stops have been described for specific cases, but their widespread impact has been overlooked. Start-stop elements occur in the 5UTR of 1, 417 human genes and are more often occupied with a ribosome than canonical uORFs or control sequences. Start-stops efficiently halt ribosomes without evidence for accelerated RNA turnover, therefore acting as a barrier for the scanning of the small ribosomal subunit and repressing downstream translation. Our results suggest a model by which the ribosome undergoes repeated cycles of termination and partial ribosomal recycling, during which the large subunit detaches, but the 40S subunit with the Met-tRNAiMet remains associated with the mRNA to be rejoined by the 60S subunit. Start-stop elements occur in many transcription factors and signaling genes, and affect cellular fate via different routes. We investigate the start-stop element in several genes, i.e. MORF4L1, SLC39A1, and PSPC1, and in more detail in ATF4.

systems biology↗