Biology subjects

Mandl, J. N.

Publications and source records attributed to Mandl, J. N..

9 recordsLinked to original sources

bioRxiv2026

A human-in-the-loop approach for faster cell tracking

Traditional cell tracking methods focus on fully automated tracking. The quality of the generated tracks, however, is heavily influenced by factors such as cell speed and density. In complex scenarios where track correctness is essential, an efficient and reliable tool for manual track correction remains a key component of the cell tracking process. Most tracking tools that allow for such manual correction do so only as a post-processing step, using human feedback to correct one track error at a time -- without improving the quality of other tracks in the dataset. This highlights the need for a more efficient track correction method that iteratively integrates human feedback into the automated tracking process. In this paper we propose a human-in-the-loop approach to cell tracking and investigate the extent to which a tracking algorithm can learn from human input during the tracking process. We combine a graph representation of cell detections, Dijkstra's shortest path algorithm, and a neural network that predicts cell displacement to generate initial track suggestions. We introduce a tool that enables human feedback on individual tracks suggested by the algorithm; this feedback is then propagated to improve subsequent track generation. Compared to the traditional approach of fully automated tracking with correction as a post-processing step, our human-in-the-loop tracking framework reduces the number of corrections required. Finally, we show how this approach can be integrated with existing state-of-the-art tracking algorithms by using pre-generated tracks as a prior, improving the quality of tracks suggested to the human annotator.

bioinformatics↗

bioRxiv2025

Within-host viral evolution varies with T cell receptor repertoire diversity independently of viral mutation rates

The specific T cell receptors (TCRs) present in an individual determine which antigens can be recognized, and hence a repertoire comprised of a vast number of unique TCRs ensures an effective T cell response can be mounted against a broad range of potential pathogens encountered. To evade the T cell response, pathogens, and viruses in particular, can accrue epitope escape mutations, establishing a host-pathogen tug-of-war between T cell-mediated control and viral evolution. Indeed, the evolutionary significance of TCR diversification in mammals is underscored by the sophisticated molecular machinery - spanning from somatic V(D)J recombination through non-templated nucleotide additions - that establish the TCR repertoire. Yet, whether greater oligoclonality among responding T cells, as is the case for elderly or immunocompromised individuals, might therefore accelerate pathogen immune escape remains unclear. Here, we constructed a computational model of T cell-mediated viral evolution to investigate how the number of unique virus-specific T cells clones impacts the balance between curtailing viral load through cross-reactivity to mutant strains on the one hand, versus promoting the generation of escape variants on the other. The model recapitulated prior experimental findings, such as T cell-dependent emergence of new viral mutants and the progressive decrease in the number of T cell clones present in the response over time. Our model simulations suggested that oligoclonality in the virus-specific T cell response can, if coupled with a resulting increase in viral replication, maximize viral immune escape despite constant mutation rates revealing a mechanism for how viruses with comparable mutation rates can nonetheless exhibit dramatically different adaption rates within hosts. Taken together, the model results suggest that variations in TCR repertoire diversity, and consequently in the number of pathogen-specific T cell clones within an individual, can have direct, non-linear impacts on viral immune escape.

immunology↗

bioRxiv2024

Cooperative motility emerges in crowds of T cells but not neutrophils

Interacting, self-propelled particles are prone to jamming when crowded. This well-described phenomenon is shared by diverse systems including cars, animal colonies, and pedestrians. T cells, essential effectors of adaptive immunity, seemingly defy this principle: the rapid migration enabling their protective function persists even in tightly packed tissue environments - from the thymus where T cells develop, to lymphoid organs they survey for antigen, to tissues they clear from infection. Here we studied T cell crowds by combining experiments of T cells migrating in microfluidic devices with in silico models. We observed that while single T cells are highly heterogeneous in their motility, in crowds they synchronized their speeds and formed stable, motile trains. Our models showed that the emergence of this flocking-like behavior can be explained by a combination of two interaction mechanisms at the cell-cell interface: adhesion maintains cohesive T cell groups, and force transmission accelerates slower cells. Not all immune cells flock when they are crowded: neutrophils in the same settings slowed down with increasing cell density. Thus, cooperative motion may enable T cells to remain motile in densely packed tissue environments, preventing jams that curtail the motion of other crowded systems.

cell biology↗

bioRxiv2024

DOCK8 regulates a mechanosensitive actin redistribution that maintains immune cell cohesion and protects the nucleus during migration

Immune cells navigate through complex 3-dimensional tissue architectures, utilizing an amoeboid mode of migration, characterized by extensive cellular deformation, low adhesion, and high cell velocities. In the absence of expression of Dedicator of Cytokinesis 8 (Dock8), a gene identified with loss-of-function mutations in immunodeficiency, cells become entangled during migration through dense, confined environments and consequently undergo catastrophic cell rupturing, while migration on 2D surfaces remains entirely intact. Here we investigated the specific cytoskeletal defect of Dock8-deficient activated T cells, showing that even prior to entanglement they display a striking difference in F-actin distribution compared to wild type (WT) cells. We describe a central pool of F-actin in WT murine and human T cells which is absent in Dock8 KO T cells, and determine that the relocalization of F-actin is a mechanoresponsive circuit, emerging only when cells are very confined. Our works shows that the central actin pool is nucleo-protective, reducing nuclear deformation and DNA damage during confined migration. We identify the Hippo-pathway kinase Mst1 as a co-mediator of this mechanosensitive pathway in conjunction with Dock8, allowing for cell cohesion and survival during migration through complex environments.

immunology↗

bioRxiv2022

Machine learning analysis of the T cell receptor repertoire identifies sequence features that predict self-reactivity

The T cell receptor (TCR) determines the specificity and affinity for both foreign and self-peptides presented by MHC. It is established that self-pMHC reactivity impacts T cell function, but it has been challenging to identify TCR sequence features that predict T cell fate. To discern patterns distinguishing TCRs from naive CD4+ T cells with low versus high self-pMHC reactivity, we used data from 42 mice to train a machine learning (ML) algorithm that predicts self-reactivity directly from TCR{beta} sequences. This approach revealed that n-nucleotide additions and acidic amino acids weaken self-reactivity. We tested our ML predictions of TCR{beta} sequence self-reactivity using retrogenic mice. Extrapolating our analyses to independent datasets, we found high predicted self-reactivity for regulatory CD4+ T cells and low predicted self-reactivity for T cells responding to chronic infection. Our analyses suggest a potential trade-off between repertoire diversity and self-reactivity intrinsic to the architecture of a TCR repertoire.

immunology↗

bioRxiv2022

Chronic infection control relies on T cells with lower foreign antigen binding strength generated by N-nucleotide diversity

The pathogens to which T cells respond is determined by the T cell receptors (TCRs) present in an individuals repertoire. Although more than 90% of the TCR repertoire is generated by terminal deoxynucleotidyl transferase (TdT)-mediated N-nucleotide addition during V(D)J recombination, the benefit of TdT-modified TCRs remains unclear. Here, we computationally and experimentally investigated whether TdT systematically modifies the affinity distribution of a TCR repertoire in ways that impacts acute or chronic infection. Our computational model predicts a shift toward low-affinity T cells over time during chronic, but not acute, infections. Elimination of low-affinity T cells in silico substantially delayed chronic infection clearance. Corroborating an affinity-centric benefit for TCR diversity, we showed that infection of TdT-deficient mice delayed the clearance of a chronic viral pathogen, while acute viral control was unaffected. Our data thus suggest that TdT-mediated TCR diversity is of particular benefit in the control of prolonged pathogen replication.

immunology↗

bioRxiv2021

Pre-existing chromatin accessibility and gene expression differences among naïve CD4+ T cells influence effector potential

CD4+ T cells have a remarkable potential to differentiate into diverse effector lineages following activation. Here, we probed the heterogeneity present among naive CD4+ T cells before encountering their cognate antigen to ask whether their effector potential is modulated by pre-existing transcriptional and epigenetic differences. Using single-cell RNA sequencing, we showed that key drivers of variability are genes involved in T cell receptor (TCR) signaling. Using CD5 expression as a read-out of the strength of tonic TCR interactions with self-peptide MHC, and sorting on the ends of this self-reactivity spectrum, we find that pre-existing transcriptional differences among naive CD4+ T cells impact follicular helper cell (TFH) versus non-TFH effector lineage choice. Moreover, our data implicate TCR signal strength during thymic development in establishing differences in naive CD4 T cell chromatin landscapes that ultimately shape their effector potential.

immunology↗

bioRxiv2018

Robust self-nonself discrimination requires negative T cell selection on non-random peptides

Self-foreign discrimination by the immune system was long thought to arise because negative selection in the thymus silences self-reactive T cells. Yet recent data show that this silencing is remarkably incomplete. Here we ask how a repertoire containing many self-reactive cells can nevertheless discriminate self from foreign. We address this question using realistic-scale computational models of the T cell repertoire. Our models show that when foreign peptides dif-fer systematically from self, moderate T cell cross-reactivity skews the post-selection repertoire towards foreign recognition. When no such systematic differences exist, self-foreign discrim-ination is only possible if peptide presentation in the thymus minimizes the co-occurrence of similar, redundant self peptides. These results imply that negative selection needs to be based on non-random self peptides to allow robust self-foreign discrimination for both self-similar and -dissimilar pathogens.

immunology↗

bioRxiv2017

CYRI1-mediated inhibition of RAC1 signalling restricts Salmonella Typhimurium infection

Salmonella presents a global public health concern. Central to Salmonella pathogenicity is an ability to subvert host defence mechanisms through bacterial effectors that target key host proteins implicated in restricting infection. Thus, to gain insight into host-pathogen interactions governing Salmonella infection, a thorough understanding of host defence mechanisms is needed. To tackle this, we performed an in vivo genome-wide ENU mutagenesis screen to uncover novel host defence proteins. Through this screen we identified an uncharacterised protein, which we name CYRI1 (CYFIP-related RAC1 Interacting protein 1) that serves as a Salmonella resistance factor. We show that CYRI1 binds to the small GTPase RAC1 through a conserved domain present in CYFIP proteins, which are known RAC1 effectors that stimulate actin polymerisation. However, unlike CYFIP proteins, CYRI1 negatively regulates RAC1-driven actin cytoskeleton remodelling, thereby attenuating processes such as phagocytosis and cell migration. This, in turn, enables CYRI1 to counteract Salmonella at various stages of infection, including bacterial entry into epithelial cells, internalisation into myeloid-derived phagocytes as well as phagocyte-mediated bacterial dissemination. Together, this outlines a novel host defence mechanism that is crucial for determining bacterial fate.

cell biology↗