Biology subjects

Lang, V.

Publications and source records attributed to Lang, V..

5 recordsLinked to original sources

bioRxiv2026

A pro-inflammatory effector-memory T cell program links peripheral EBV priming to CNS autoimmunity

T and B cell-mediated immunosurveillance of the central nervous system (CNS) can become maladaptive in multiple sclerosis (MS). Epstein-Barr virus (EBV) is a likely driver of MS, yet how exactly EBV-specific T cells contribute remains unclear. We generated an antigen-resolved atlas of blood and cerebrospinal fluid (CSF) T cells from untreated MS patients and controls. T cell clones carrying a GZMK effector-memory program in blood were CSF-biased, particularly in MS, and associated with EBV reactivity. In CSF, EBV-reactive GZMK CD8 T cells engaged B lineage cells. Activated CD8 T cells promoted atypical B cell and plasmablast formation, whereas GZMK-enriched effector-memory cells induced IL-6 and IL-8 release from myeloid cells. Together, these findings identify an infection-imprinted, CNS-biased state and support a model in which EBV-specific CD8 T cells contribute to inflammation through a non-canonical mode of B cell and myeloid cell activation.

immunology↗

bioRxiv2026

Natural microbial exposure imposes layered constraints on epithelial and type 2 immunity

The tuft cell-ILC2 amplification circuit has emerged as a central paradigm of anti-helminth immunity in laboratory animals, driving the so-called weep and sweep response, required for parasite expulsion. Yet soil-transmitted helminths (STHs) commonly establish chronic infections in humans. Whether tuft cell expansion is required for parasite clearance under naturalistic conditions remains unknown. Here, using wildlings, a naturalized mouse model exposed from birth to complex microbial communities and pathogens, we re-investigated anti-STH immunity in the context of ecological realism. Following infection with Nippostrongylus brasiliensis, specific pathogen-free (SPF) mice mounted markedly amplified type 2 responses in both lung and intestine compared to wildlings. In the intestine, SPF mice mounted robust tuft cell expansion, IL-25 production, ILC2 accumulation, and goblet cell hyperplasia. In contrast, infected wildlings exhibited delayed parasite expulsion, limited tuft cell expansion, reduced IL-25 and ILC2 responses, and attenuated goblet cell expansion. Wildling tuft cells, but not goblet cells, displayed markedly reduced expansion in response to succinate or exogenous IL-13, indicating selective hypo-responsiveness of the epithelial sensory compartment. Microbial transfer into adult SPF mice selectively conferred tuft cell hypo-responsiveness without impairing ILC2 accumulation or goblet cell expansion. Tuft cell hypo-responsiveness in wildlings and FMT recipients was associated with enrichment of fermentative bacteria and increased levels of the short chain fatty acids acetate and propionate. Together, these findings indicate that ecological microbial exposure imprints systemic type 2 immunity during early-life, whereas epithelial responsiveness remains plastic and microbiome-dependent, thereby revealing regulatory constraints not evident under SPF conditions. One Sentence SummaryOur findings reveal that in a naturalized immune-microbiome context, intestinal tuft cells are surprisingly hypo-responsive, highlighting how environmental microbial exposure can calibrate type 2 immunity and helminth resistance.

immunology↗

bioRxiv2026

Advanced 3D spheroid-based skin models and deep-learning based image analysis enable in-depth investigation of keratinocyte differentiation and barrier function

To date, a panel of different biological models have been used in skin research, ranging from in vivo testing to 2D and 3D cultures. Among these, organotypic skin models represent the current gold standard for preclinical dermatology and toxicology studies. However, they are variable in quality and require long maturation times and a lot of work and cells, the latter often of primary origin. Here, we propose dermal-epidermal spheroids as an alternative model that balances physiological relevance and throughput. Next to corresponding full thickness skin models, different fibroblast/keratinocyte coculture spheroids were generated. These used the commonly employed HaCaT cells as well as two recently immortalized keratinocyte cell lines, NHK-SV/TERT and NHK-E6/E7. To investigate their differentiation with detailed spatio-temporal resolution, a deep-learning segmentation-based pipeline, capable of revealing nuclear morphology and positioning as well as marker expression with single-cell precision, was developed and applied. Moreover, the formation of a functional barrier was assessed by live-imaging of Lucifer yellow diffusion. These experiments identified the NHK-E6/E7 cell line as the most and HaCaT cells as the least suitable alternative to primary keratinocytes in both spheroids and full thickness models. Furthermore, NHK-based coculture spheroids displayed functional maturation, including stratification, cornification, and barrier formation, closely recapitulating these features of corresponding full thickness models. Given the scalability and compatibility with automation, these micro-skin fibroblast/NHK-based 3D coculture spheroids might represent a promising new platform for pharmaceutical, cosmetic, and toxicological testing.

bioengineering↗

bioRxiv2025

The Cancer/Testis Antigen FATE1 Antagonizes Fission and Preserves Mitochondrial Network Integrity under Cytotoxic Stress

FATE1 (Fetal and Adult Testis Expressed 1), also known as BJ-HCC-2, is a cancer-testis antigen with highly restricted expression in normal tissues but aberrant activation in diverse tumor types, where it localizes to both the outer mitochondrial membrane and the endoplasmic reticulum (ER) and functions as a key survival factor. Although FATE1 shares sequence homology with the mitochondrial fission factor Mff, its role in regulating mitochondrial architecture has not been mechanistically defined. Here, we identify FATE1 as a novel modulator of mitochondrial morphology that acts through a mechanism distinct from Mff. Unlike Mff, FATE1 does not recruit Drp1 to mitochondria and therefore lacks canonical fission activity. Instead, FATE1 promotes mitochondrial hyperfusion and protects against mitochondrial fragmentation triggered by cytokines and mitochondrial uncoupler treatment. The pro-fusion activity of FATE1 requires its mitochondrial targeting and interaction with Mitofusin-2 (Mfn2). Our findings establish FATE1 as a cancer-selective regulator of mitochondrial dynamics that antagonizes fission and preserves network integrity under cytotoxic stress, revealing a potential mechanism by which tumor cells evade mitochondria-driven apoptotic signaling.

cell biology↗

bioRxiv2019

Susceptibility rhythm to bacterialendotoxin in myeloid clock-knockout mice

Local circadian clocks are active in most cells of our body. However, their impact on circadian physiology is still under debate. Mortality by endotoxic (LPS) shock is highly time-of-day dependent and local circadian immune function such as the cytokine burst after LPS challenge has been assumed to be causal for the large differences in survival. Here, we investigate the roles of light and myeloid clocks on mortality by endotoxic shock. Strikingly, mice in constant darkness (DD) show a three-fold increased susceptibility to LPS as compared to mice in light-dark conditions. Mortality by endotoxic shock as a function of circadian time is independent of light-dark cycles as well as myeloid CLOCK or BMAL1 as demonstrated in conditional knockout mice. Unexpectedly, despite the lack of a myeloid clock these mice still show rhythmic patterns of pro- and anti-inflammatory cytokines such as TNF, MCP-1, IL-18 and IL-10 in peripheral blood as well as time-of-day and site dependent traffic of myeloid cells. We speculate that systemic time-cues are sufficient to orchestrate innate immune response to LPS by driving immune functions such as cell trafficking and cytokine expression.

immunology↗