Biology subjects

Nasr, N.

Publications and source records attributed to Nasr, N..

4 recordsLinked to original sources

bioRxiv2025

Blinatumomab-driven T-cell activation in αβ and γδ T-cell subsets: Insights from in vitro assays

Blinatumomab (BLN) is a bispecific T-cell engager that has revolutionized the treatment of B-cell precursor acute lymphoblastic leukemia (BCP-ALL), significantly improving outcomes in both adults and children. By simultaneously binding to CD19 on B cells and CD3 on T cells, BLN triggers target cell-dependent T-cell activation, resulting in the cytolysis of CD19+ BCP-ALL cells. Despite the remarkable clinical advancements achieved with BLN, the immunological mechanisms underlying treatment response or failure remain poorly characterized. {gamma}{delta} T cells are attractive candidates for adoptive T-cell therapy due to potent cytotoxicity, capacity to present antigens, broad lysis of different tumor entities, and low alloreactivity. Because {gamma}{delta} T cells can also be redirected by BLN, we systematically studied BLN-driven effector functions of conventional {beta} and unconventional {gamma}{delta} T cells. We evaluated cytotoxicity and cytokine/effector release in freshly isolated and in vitro-expanded {beta} and {gamma}{delta} T cells from healthy adults against CD19 BCP-ALL lines (NALM-6, HAL-01), and profiled dynamic phenotypic alterations by multiparametric flow cytometry. CD19 targets were consistently reduced in the presence of BLN. Freshly isolated {beta}, especially CD8, displayed superior BLN-mediated cytotoxicity as compared to {gamma}{delta} T cells, with donor-dependent variability in {gamma}{delta} killing. Notably, zoledronate-expanded V{gamma}9V{delta}2 {gamma}{delta} T-cell lines achieved cytotoxicity comparable to PHA-expanded {beta} cells. However, {gamma}{delta} T-cell-killing benefited from higher BLN concentration when challenged with high tumor load. BLN induced CD3 down-modulation in {beta} T cells but not in {gamma}{delta} T cells, alongside higher soluble Fas ligand in {beta} cultures, consistent with stronger early activation, preceding activation-induced cell death. {gamma}{delta} T cells showed no such changes, suggesting reduced susceptibility to activation-induced cell death. Single-cell RNA and flow analyses corroborated these findings, showing robust activation/exhaustion programs in {beta} T cells and a stable effector-memory state with low checkpoint expression in {gamma}{delta} T cells. Together, these data reveal subset-specific BLN responses and support expanded V{gamma}9V{delta}2 {gamma}{delta} T cells as a rational adoptive partner to BLN -- particularly in settings of favorable antigen density/low tumor burden -- providing complementary cytotoxicity with potentially reduced inflammatory liability. These findings provide a framework for combining {gamma}{delta} T-cell-based therapies in BLN-treated patients for improving BLN efficacy in BCP-ALL patients.

immunology↗

bioRxiv2020

Integrating cyanobacterial flavodiiron proteins within the chloroplast photosynthetic electron transport chain maintains carbohydrate turnover and enhances drought stress tolerance in barley

Chloroplasts, the sites of photosynthesis in higher plants, have evolved several means to tolerate short episodes of drought stress through biosynthesis of diverse metabolites essential for plant function, but these become ineffective when the duration of the stress is prolonged. Cyanobacteria are the closest bacterial homologs of plastids with two photosystems to perform photosynthesis and to evolve oxygen as a byproduct. The presence of Flv genes encoding flavodiiron proteins has been shown to enhance stress tolerance in cyanobacteria. Here, the products of Synechocystis genes Flv1 and Flv3 were expressed in chloroplasts of barley in an attempt to support the growth of plants exposed to drought. The heterologous expression of both Flv1 and Flv3 accelerated days to heading, increased biomass, promoted the number of spikes and grains per plant, and improved grain yield of barley plants exposed to drought. Improved growth correlated with enhanced availability of soluble sugars, a higher turnover of amino acids and the accumulation of lower levels of proline in the leaf. Flv1 and Flv3 maintained the energy status of the leaves in the stressed plants by converting sucrose to glucose and fructose, immediate precursors for energy production to support plant growth under drought. The results suggest that sugars and amino acids play a fundamental role in the maintenance of the energy status and metabolic activity to ensure growth and survival under stress conditions, that is, water limitation in this particular case. Engineering chloroplasts by introducing Flv genes, therefore, has the potential to improve plant productivity wherever drought stress represents a significant production constraint.

plant biology↗

bioRxiv2020

Identification of HIV-Transmitting Sub-Epithelial Mononuclear Phagocytes in Human Anogenital and Colorectal Tissues

Tissue mononuclear phagocytes (MNP) are specialised in pathogen detection and antigen presentation. They are the first cells of the immune system to encounter HIV and play a key role in transmission as they deliver the virus to CD4 T cells, which are the primary HIV target cell in which the virus undergoes replication. Most studies have investigated the role that epithelial MNPs play in HIV transmission but, as mucosal trauma and inflammation are strongly associated with HIV transmission, it is also important to examine the role that sub-epithelial MNPs play. Sub-epithelial MNPs are present in a diverse array of subsets which differ in their function and the pathogens they detect. Understanding how specific subsets interact with HIV and deliver the virus to CD4 T cells is therefore of key importance to vaccine and microbicide development. In this study we have shown that, after topical application, HIV can penetrate to interact with sub-epithelial resident myeloid cells in anogenital explants and defined the full array of MNP subsets that are present in all the human anogenital and colorectal sub-epithelial tissues that HIV may encounter during sexual transmission. In doing so we have identified two subsets that preferentially take up HIV, become infected and transmit the virus to CD4 T cells; CD14+CD1c+CD11c+ monocyte-derived dendritic cells and langerin-expressing dendritic cells 2 (DC2).

immunology↗

bioRxiv2019

Piezo1 is required for outflow tract and aortic valve development.

Aims-During embryogenesis, the onset of circulatory blood flow generates a variety of hemodynamic forces which reciprocally induce changes in cardiovascular development and performance. It has been known for some time that these forces can be detected by as yet unknown mechanosensory systems which in turn promote cardiogenic events such as outflow tract and aortic valve development. PIEZO1 is a mechanosensitive ion channel present in endothelial cells where it serves to detect hemodynamic forces making it an ideal candidate to play a role during cardiac development. We sought to determine whether PIEZO1 is required for outflow tract and aortic valve development. Methods and results-By analysing heart development in zebrafish we have determined that piezo1 is expressed in the developing outflow tract where it serves to detect hemodynamic forces. In particular, we have found that mechanical forces generated during the cardiac cycle activate Piezo1 which triggers nitric oxide to be released in the outflow tract. Consequently, disrupting Piezo1 signalling leads to defective outflow tract and aortic valve development and indicates this gene may be involved in the etiology of congenital heart diseases. Based on these findings, we analysed genomic data generated from a cohort of bicuspid aortic valve patients and identified 3 probands who each harboured a novel variant in PIEZO1. Subsequent in vitro and in vivo assays indicates that these variants behave as dominant negatives leading to an inhibition of normal PIEZO1 mechanosensory activity and defective aortic valve development. Conclusion-These data indicate that the mechanosensitive ion channel piezo1 is required for OFT and aortic valve development and, furthermore, dominant negative variants of PIEZO1 appear to be associated with BAV in humans.

developmental biology↗