Biology subjects

Bediaga, N. G.

Publications and source records attributed to Bediaga, N. G..

5 recordsLinked to original sources

bioRxiv2024

Activated NK cells with a predominance of inhibitory receptors and a decidual-like phenotype expand after autologous HSCT in children with tumors.

Early immune reconstitution after autologous hematopoietic stem cell transplantation (autoHSCT) is associated with a better outcome in a variety of cancers. NK cells constitute the first lymphocyte subset to recover in the blood after autoHSCT. We have in-depth characterized them in pediatric patients with different tumors and found that, immediately after autoHSCT, NK cells transiently acquired a decidual-like phenotype, were more immature and activated, and exhibited an increased expression of inhibitory receptors, while activating receptors levels were diminished. This activated and decidual-like phenotype was characterized by increased CD56, CD9, CD49a, CD151, CD38, HLA-DR and CD55 expression. We also determined plasma levels of several cytokines and found that their concentrations were associated with the observed changes in NK cells phenotype. In vitro experiments, including flow cytometry and single-cell RNA sequencing (scRNA-seq), recapitulated the changes observed in NK cells early after autoHSCT. Specifically, results revealed that the combination of IL-15 and TGF-{beta} induced, at least partially, this distinctive phenotype on NK cells after autoHSCT. Finally, we have observed a positive correlation between relapse and the percentage of CD56dim NK cells shortly after autoHSCT in our cohort of pediatric patients. Altogether, our work is of relevance to understand the physiopathology of NK cells during the immune system reconstitution after autoHSCT in children and potentially help in the management of these patients.

immunology↗

bioRxiv2022

CIS calibrates GM-CSF signalling strength to regulate macrophage polarization via a STAT5-IRF8 axis

The cytokine granulocyte-macrophage-colony stimulating factor (GM-CSF) possesses the ability to differentiate macrophages (MOs) with opposing functions, namely proinflammatory M1-like and immunosuppressive M2-like. Despite the importance and opposing functional outcomes of these processes, the intrinsic mechanism that regulates the functional polarization of MOs under GM-CSF signaling remains elusive. Here we show that GM-CSF induced MOs polarisation resulted in the expression of the Cytokine-inducible SH2-containing protein (CIS), and that CIS deficiency diverted differentiation of monocytes into immunosuppressive M2-like MOs expression. CIS deficiency resulted in the hyperactivation of the JAK-STAT5 signaling pathway, consequently promoting the downregulation of the transcription factor Interferon Regulatory Factor 8 (IRF8). Loss and gain of function approaches highlighted IRF8 as a critical instructor of the M1-like polarisation program. In vivo, CIS deficiency led to skewing to M2-like macrophages, which induced strong Th2 immune responses characterised by the development of severe experimental asthma. Collectively, we reveal a CIS-censored mechanism interpreting the opposing actions of GM-CSF in MO differentiation and uncovering its role in controlling allergic inflammation.

immunology↗

bioRxiv2020

Chromosomes distribute randomly to, but not within, human neutrophil nuclear lobes

The proximity pattern and radial distribution of chromosome territories within spherical nuclei are well understood to be random and non-random, respectively. Whether this distribution pattern is conserved in the partitioned or lobed nuclei of polymorphonuclear cells is unclear. Here we use chromosome paint technology and a novel high-throughput imaging analysis pipeline to examine the chromosome territories of all 46 chromosomes in hundreds of single human neutrophils - an abundant and famously polymorphonuclear immune cell. By comparing the distribution of chromosomes to randomly shuffled controls, and validating with orthogonal chromosome conformation capture technology, we show for the first time that all human chromosomes randomly distribute to neutrophil nuclear lobes, while maintaining a non-random radial distribution within these lobes. Furthermore, by leveraging the power of this vast dataset, we are able to reveal characteristics of chromosome territories not detected previously. For example, we demonstrate that chromosome length correlates with three-dimensional volume not only in neutrophils but other human immune cells. This work demonstrates that chromosomes are largely passive passengers during the neutrophil lobing process, but are able to maintain their macro-level organisation within lobes. Furthermore, the random distribution of chromosomes to the naturally partitioned nuclear lobes suggests that specific transchromosomal interactions are unimportant in mature neutrophils.

immunology↗

bioRxiv2020

Activation-induced re-organization of chromatin in human T cells

Remodelling of chromatin architecture is known to regulate gene expression and has been well characterized in cell lineage development but less so in response to cell perturbation. Activation of T cells, which triggers extensive changes in transcriptional programs, serves as an instructive model to elucidate how changes in genome organization orchestrate gene expression in response to cell perturbation. To characterize coordinate changes at different levels of chromatin architecture, we analysed chromatin accessibility, chromosome conformation and gene expression after activation of human T cells. T cell activation led to widespread changes in chromatin interactions and accessibility that were mostly shared between CD4+ and CD8+ T cells. Differential chromatin interactions were associated with upregulation or downregulation of linked target genes. Moreover, activation was associated with the formation of shorter chromatin interactions, partitioning of topologically associating domains (TADs) and acquisition of new TAD boundaries characterized by higher nucleosome occupancy, and lower chromatin accessibility and gene expression. These findings render an integrated and multiscale characterization of activation-induced re-organization of chromatin architecture underlying gene transcription in human T cells.

genetics↗

bioRxiv2017

No kissing in the nucleus: Unbiased analysis reveals no evidence of trans chromosomal regulation of mammalian immune development

It has been proposed that interactions between mammalian chromosomes, or transchromosomal interactions (also known as kissing chromosomes), regulate gene expression and cell fate determination. Here we aimed to identify novel transchromosomal interactions in immune cells by high-resolution genome-wide chromosome conformation capture. Although we readily identified stable interactions in cis, and also between centromeres and telomeres on different chromosomes, surprisingly we identified no gene regulatory transchromosomal interactions in either mouse or human cells, including previously described interactions. We suggest that advances in the chromosome conformation capture technique and the unbiased nature of this approach allow more reliable capture of interactions between chromosomes than previous methods. Overall our findings suggest that stable transchromosomal interactions that regulate gene expression are not present in mammalian immune cells and that lineage identity is governed by cis, not trans chromosomal interactions.

genomics↗