Biology subjects

van der Veeken, J.

Publications and source records attributed to van der Veeken, J..

5 recordsLinked to original sources

bioRxiv2025

ArchVelo: Archetypal Velocity Modeling for Single-cell Multi-omic Trajectories

Inferring dynamic cellular processes from static single-cell measurements remains a central challenge in genomics. Here we introduce ArchVelo, a new method for modeling gene regulation and inferring cell trajectories using single-cell simultaneous chromatin accessibility (scATAC-seq) and transcriptomic (scRNA-seq) profiling. ArchVelo represents chromatin accessibility as a set of archetypes--shared regulatory programs--and models their dynamic influence on transcription. Compared to previous methods, ArchVelo improves inference accuracy and gene-level latent time alignment, and enables identification of the underlying transcription factor activity. We benchmark ArchVelo on developing mouse brain and human hematopoiesis datasets and apply it to CD8 T cells responding to viral infection, revealing distinct trajectories of differentiation and proliferation. Focusing on the progenitor CD8 T cell population with key roles in sustaining immune responses and translationally linked to immunotherapy outcomes, we identify a previously uncharacterized differentiation trajectory from Ccr6- to Ccr6+ progenitors, shared between acute and chronic infection. In sum, ArchVelo provides a principled framework for modeling dynamic gene regulation in multi-omic single-cell data across biological systems.

genomics↗

bioRxiv2025

Single-cell multiomics reveals archetypal regulatory programs shared across CD4 and CD8 T cell subsets in viral infection

T cells protect against pathogens and tumors and can differentiate into various functionally distinct subsets. While each subset exhibits a characteristic epigenomic and transcriptional profile, essential immune functions such as self-renewal, expansion, cytokine production, and cytotoxicity are common to multiple subsets and therefore must be programmed via shared regulatory mechanisms. To uncover these regulatory "archetypes", we integrated a new single-cell multiomic (scATAC+RNA-seq) dataset for CD4 and CD8 T cells responding to acute and chronic viral infection with a comprehensive compendium of bulk ATAC-seq data. Our analysis revealed that T cell identity is governed by a modular architecture, where distinct transcription factors drive the reuse of regulatory archetypes across T cell subsets and lineages. Notably, translationally important progenitor Tcf1+ CD8 T cells, critical for sustaining CD8 T cell responses and present in both acute and chronic infection, exhibited a composite regulatory state combining a CD8 T cell exhaustion program and, unexpectedly, a follicular helper CD4 T cell program. In sum, this resource will aid mechanistic dissection of adaptive immunity and immunotherapy design, and the framework will be broadly applicable across biological systems. Highlights- Single-cell multiomics and ATAC-seq atlas reveal T cell regulatory archetypes - A unified progenitor Tcf1+ CD8 T cell population is shared by acute and chronic infection - Progenitor CD8 T cell identity combines CD8 exhaustion and CD4 Tfh regulatory programs - A Tfh-like differentiation gradient underlies heterogeneity in progenitor CD8 T cells

immunology↗

bioRxiv2025

Caffeine-regulated molecular switches for functional control of CAR T cells in vivo

The limited controllability of CAR T cells in patients represents a key challenge of this highly potent immunotherapy. A molecular ON-switch, which can be regulated with a non-toxic and readily available small molecule drug, would represent a major advance towards controllable CAR T therapeutics. For that purpose, we engineered caffeine-responsive heterodimeric ON-switches (CaffSwitches) and demonstrate their high caffeine-dependency and virtually absent leakiness. When incorporating these CaffSwitches into CARs, the resulting CaffCARs were efficiently activated by caffeine concentrations achieved in human plasma after drinking one cup of coffee. Moreover, CaffCAR T cells also showed efficient tumor clearance in an in vivo mouse model, which was completely abolished in the absence of caffeine. This tight control was even observed with c-Jun overexpressing CaffCAR T cells, despite their massive expansion. Together, we anticipate that these novel CaffSwitches will be valuable tools for the development of safe and efficient next generation CAR T cells.

synthetic biology↗

bioRxiv2022

FoxP3 can fold into two distinct dimerization states with divergent functional implications for T cell homeostasis

FoxP3 is an essential transcription factor (TF) for immunologic homeostasis, but how it utilizes the common forkhead DNA-binding domain (DBD) to perform its unique function remains poorly understood. We here demonstrate that, unlike other known forkhead TFs, FoxP3 forms a head-to-head dimer using a unique linker (Runx1-binding region, RBR) preceding the forkhead domain. Head-to-head dimerization confers distinct DNA-binding specificity and creates a docking site for the cofactor Runx1. RBR is also important for proper folding of the forkhead domain, as truncation of RBR induces domain-swap dimerization of forkhead, which was previously considered the physiological form of FoxP3. Rather, swap-dimerization impairs FoxP3 function, as demonstrated with the disease-causing mutation R337Q, while a swap-suppressive mutation largely rescues R337Q-mediated functional impairment. Altogether, our findings suggest that FoxP3 can fold into two distinct dimerization states: head-to-head dimerization representing functional specialization of an ancient DBD and swap-dimerization with impaired functions.

immunology↗

bioRxiv2020

A unified atlas of CD8 T cell dysfunctional states in cancer and infection

CD8 T cells play an essential role in defense against viral and bacterial infections and in tumor immunity. Deciphering T cell loss of functionality is complicated by the conspicuous heterogeneity of CD8 T cell states described across different experimental and clinical settings. By carrying out a unified analysis of over 300 ATAC-seq and RNA-seq experiments from twelve independent studies of CD8 T cell dysfunction in cancer and infection we defined a shared differentiation trajectory towards terminal dysfunction and its underlying transcriptional drivers and revealed a universal early bifurcation of functional and dysfunctional T cell activation states across models. Experimental dissection of acute and chronic viral infection using scATAC-seq and allele-specific scRNA-seq identified state-specific transcription factors and captured the early emergence of highly similar TCF1+ progenitor-like populations at an early branch point, at which epigenetic features of functional and dysfunctional T cells diverge. Our atlas of CD8 T cell states will facilitate mechanistic studies of T cell immunity and translational efforts.

genomics↗