Brueck, J. | bioRxiv Science

bioRxiv2026

Neonatal liver niches program T cell tolerance

After birth, the immune system must learn to tolerate a rapidly changing milieu of commensals and self while remaining ready for pathogens. Here we characterize the neonatal liver as a central hub in this process: In postnatal week 1-2, the liver hosts a developmentally encoded, microbiota-independent expansion of regulatory T cells (Tregs) that coexists with microbiota-tuned conventional wave of activated CD4 T cells (Tconvs). Mechanistically, the Treg expansion is governed by MHCII-mediated antigen presentation by CCR7+ cDC1s, which establish tolerogenic DC:T cell clusters in the liver parenchyma, allowing for local expansion and control via PD-L1 checkpoints that selectively increase Tregs without unleashing Tconvs. Importantly, this transient, neonatal program predisposes hepatotropic viral infections to progress toward chronic disease but also protects the adult liver from steatotic disease. These data position the neonatal liver as a unique site of early life T-cell education with timing-sensitive implications for early-life interventions.

immunology↗

bioRxiv2024

Non-invasive visualization of pH changes within the tumor-micro-environment by positron emission tomography

Slight changes in the pH value of the tumor microenvironment (TME) have crucial effects on host defense, metastatic behavior, immune regulation and cellular metabolism. Due to the high metabolic activity and insufficient perfusion of tumors, acidic metabolites often accumulate in tumors and can influence the pH of the TME. Several studies have shown that the acidity of the interstitial space and the relatively stable intracellular pH can influence the functions of cancer and stromal cells and their interaction with the extracellular matrix. We describe radiopharmaceutical probes for positron emission tomography (PET) that exploits the increasingly used concept of pH-dependent intratumorally cleavage of PET-tracer to release functional moieties. The radiopharmaceuticals are based on [18F]FDG, a PET tracer, routinely used, and substituents that are pH-dependently cleaved. Utilizing preclinical models, we were able to visualize small pH differences in the acidic TME of different tumors with [18F]FDG-4-methoxybenzylamine ([18F]FDG-4MBA). In vivo studies were in line with in vitro results and showed that the hemiaminal bond between FDG and a substitute is cleaved at slightly acidic pH and leads to pH dependent radiotracer uptake. In vivo neutralization of the acidic extracellular tumor pH by sodium bicarbonate treatment prevents pH-dependent cleavage of [18F]FDG-4MBA and a resulting decrease of uptake. The determination of pH differences in acidic TME may serve as a novel marker for various questions such as regulation of the response to immunotherapies. Notably, even small pH differences in the acidic TME of different tumors, in the same in vivo model, could be visualized. This is the first preclinical study to show that it is possible to visualize small pH differences in the TME of different tumors in the same mouse using hemiaminal bound [18F]FDG. Due to the facile tracer synthesis and application, this system could be well suited for translation into clinical studies to develop new strategies of pH regulation to improve the efficacy of immunotherapy in cancer patients. graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/624628v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1c338c8org.highwire.dtl.DTLVardef@1c4fc67org.highwire.dtl.DTLVardef@197036aorg.highwire.dtl.DTLVardef@1613fa2_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗