T cell non-Hodgkin lymphomas (T-NHLs) represent a heterogeneous group of highly aggressive malignancies with poor clinical outcomes1. T-NHLs originate from peripheral T lymphocytes and are frequently characterized by genetic gain-of-function variants in T cell antigen receptor (TCR) signalling molecules1–4. Although these oncogenic alterations are thought to drive TCR pathways to induce chronic proliferation and survival programmes, it remains unclear whether T cells harbour tumour suppressors that can counteract these events. Using a murine model of human T cell lymphoma, we demonstrate that the acute enforcement of oncogenic TCR signalling in lymphocytes drives the strong expansion of these cells in vivo. However, this response is short-lived and robustly counteracted by cell-intrinsic mechanisms. A subsequent genome-wide in vivo screen using T cell-specific transposon mutagenesis identified PDCD1, which encodes the inhibitory receptor Programmed Death-1 (PD-1), as a master gene suppressing oncogenic T cell signalling. Mono- and bi-allelic PDCD1 deletions are also recurrently observed in human T cell lymphomas with frequencies that can exceed 30%, indicating high clinical relevance. Mechanistically, PD-1 activity enhances PTEN levels and attenuates AKT and PKC signalling in pre-malignant cells. In contrast, a homo- or heterozygous deletion of PD-1 allows unrestricted T cell growth after an oncogenic insult and leads to the rapid development of highly aggressive lymphomas in vivo that are readily transplantable to recipients. Altogether, these results indicate that the inhibitory PD-1 receptor is a potent haploinsufficient tumour suppressor in T-NHLs that is frequently altered in human disease. These findings extend the known physiological functions of PD-1 beyond the prevention of immunopathology after antigen-induced T cell activation and have implications for T cell lymphoma therapies and for current strategies that target PD-1 in the broader context of immuno-oncology.
CEUS is an useful method which can be additionally used to clinically differentiate between malignant and benign renal lesions. CEUS shows a comparable sensitivity, specificity, PPV and NPV to MRI. In daily clinical routine, patients with contraindications for other imaging modalities can particularly benefit using this method.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive paralysis due to the loss of primary and secondary motor neurons. Mutations in the Cu/Zn-superoxide dismutase (SOD1) gene are associated with familial ALS and to date numerous hypotheses for ALS pathology exist including impairment of the blood-spinal cord barrier. In transgenic mice carrying mutated SOD1 genes, a disrupted blood-spinal cord barrier as well as decreased levels of tight junction (TJ) proteins ZO-1, occludin, and claudin-5 were detected. Here, we examined TJ protein levels and barrier function of primary blood-spinal cord barrier endothelial cells of presymptomatic hSOD1 G93A mice and bEnd.3 cells stably expressing hSOD1 G93A . In both cellular systems, we observed reduced claudin-5 levels and a decreased transendothelial resistance (TER) as well as an increased apparent permeability. Analysis of the β-catenin/AKT/forkhead box protein O1 (FoxO1) pathway and the FoxO1-regulated activity of the claudin-5 promoter revealed a repression of the claudin-5 gene expression in hSOD1 G93A cells, which was depended on the phosphorylation status of FoxO1. These results strongly indicate that mutated SOD1 affects the expression and localization of TJ proteins leading to impaired integrity and breakdown of the blood-spinal cord barrier.
BCL10/MALT1 signaling in keratinocytes is altered in human sporadic psoriasis and is a critical initiator and amplifier of skin inflammation in mouse models.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.