Biology subjects

Meister, J.

Publications and source records attributed to Meister, J..

2 recordsLinked to original sources

bioRxiv2026

Human T Cells From Resistant Hypertension Patients Promote Hypertension via TNF in humanized mice

ObjectivePreclinical studies suggest a pivotal role of adaptive immunity, particularly T cells, in hypertension. However, due to the multifactorial pathogenesis, there is still no definitive evidence for a causal role of T cells in the development of hypertension in humans. We sought to determine whether T cells from patients with treatment-resistant hypertension (TRH) directly modulate blood pressure and vascular function in vivo. MethodsPeripheral blood mononuclear cells (PBMCs) from TRH patients and healthy controls (HC) were adoptively transferred into immunodeficient NSG-(KbDb)^null mice. Hypertension was induced by angiotensin II infusion for 14 days and monitored continuously by radiotelemetry. ResultFollowing T cell engraftment, blood pressure was assessed at baseline and during AngII infusion in both groups of recipient mice. At baseline, systolic blood pressure did not differ between both groups. However, mice receiving TRH-PBMCs developed a significantly higher systolic blood pressure following AngII compared with HC-PBMC recipients. Endothelial dysfunction in isolated perfused kidneys was more pronounced in AngII-challenged TRH-PBMC recipients compared to HC-PBMC recipients. TRH-PBMC recipients displayed elevated effector memory CD4 T cells and Th17 frequencies in spleen and kidney, along with markedly increased renal expression of human T cell-derived TNF. Overnight incubation of mouse aortic rings with human TNF induced endothelial dysfunction, indicating a causal role of T cell-derived TNF. As a proof of concept, TNF inhibition attenuated AngII-induced hypertension in TRH-PBMC-engrafted mice. ConclusionT cells from patients with treatment-resistant hypertension promote an exaggerated hypertensive response and endothelial dysfunction in PBMC-engrafted humanized mice, promoted by TNF-mediated mechanisms. These findings provide evidence that T cell-derived TNF may contribute to the pathogenesis of human hypertension.

immunology↗

bioRxiv2023

TERT expression is associated with metastasis from thin primaries, exhausted CD4+ T cells in melanoma and with DNA repair across cancer entities

Telomerase reverse transcriptase (TERT) promoter mutations occur frequently in cancer, have been associated with increased TERT expression and cell proliferation, and could potentially influence therapeutic regimens for melanoma. As the role of TERT expression in malignant melanoma and the non-canonical functions of TERT remain understudied, we aimed to extend the current knowledge on both types of TERT alterations with respect to survival, further clinical and molecular parameters. Using multivariate models, TERT alterations were not consistently associated with survival in melanoma cohorts under immune checkpoint inhibition. The presence of CD4+ T cells increased with TERT expression and correlated with the expression of exhaustion markers. While the frequency of promoter mutations did not change with Breslow thickness, TERT expression was increased in metastases arising from thinner primaries. Enrichment analyses of single-cell RNA-seq showed TERT expression is associated with genes involved in cell migration and dynamics of the extracellular matrix, supporting the role of TERT during invasion and metastasis. Co-regulated genes in several bulk tumors and single-cell RNA-seq cohorts also indicated non-canonical functions of TERT related to mitochondrial DNA stability and nuclear DNA repair in line with increased TERT expression during chromothripsis (PCAWG cohort) and under hypoxic conditions (PCAWG and SKCM cohorts). Also in glioblastoma (Klughammer and PCAWG cohorts), TERT was co-expressed with DNA repair genes. Our results thus indicate a relevance of TERT expression in melanoma metastasis, T cell dysfunction and DNA repair across cancer entities. SignificanceIn addition to the frequently occurring TERT promoter mutations, we test TERT expression with respect to clinical and molecular associates, extending the canonical role of TERT in melanoma and other cancer entities.

cancer biology↗