Biology subjects

Gergelits, V.

Publications and source records attributed to Gergelits, V..

5 recordsLinked to original sources

bioRxiv2025

Probabilistic migration events drive transient tissue residency of lymphocytes during homeostasis

Tissue-resident lymphocytes form a phenotypically and functionally distinct analog to the corresponding circulatory lymphocyte populations. Residential CD8 T cells, in particular, are identified as having prolonged residence in the tissues and key functions in recall responses at tissue-environmental interfaces, although the dwell time in individual tissues has yet to be resolved. Residential CD4 T cells, regulatory T cells, B cells, and NK cells have been demonstrated to share phenotypic properties with residential CD8 T cells, but the migratory kinetics are even more poorly defined. Here we used probabilistic modelling on a large parabiosis dataset, covering multiple time-points and tissues, to calculate migration kinetics and dwell times of multiple lymphocyte subsets across a diverse set of tissues. Markov chain modelling identified distinct cell type-specific and tissue-specific residency patterns. The liver and gut were prone to prolonged residency compared to other tissue types, and a hierarchy of residency was observed with CD8 T cells and NK cells demonstrating longer residency than CD4 conventional T cells and regulatory T cells, which in turn resided in tissues longer than B cells. With few exceptions, however, average residency was at least an order of magnitude shorter than the life-span of the mouse, indicating a more dynamic form of steady-state tissue residency than usually assumed. Together these data provide a comprehensive model of a pan-tissue shared program in lymphocyte tissue residence, as well as identifying cell type- and organ-specific modification of the migratory kinetics.

immunology↗

bioRxiv2023

The tissue-resident regulatory T cell pool is shaped by transient multi-tissue migration and a conserved residency program

The tissues are the site of many of the most important immunological reactions, yet the immunology of the tissues has remained relatively opaque. Recent studies have identified Foxp3+ regulatory T cells (Tregs) in several non-lymphoid tissues. These tissue-resident populations have been ascribed unique characteristics based on comparisons to lymphoid Tregs. Here we performed a systematic analysis of the Treg population residing in non-lymphoid organs throughout the body, revealing shared phenotypes, transient residency and common molecular dependencies. Further, tissue Tregs from different non-lymphoid organs shared T cell receptor (TCR) sequences, with functional capacity to drive multi-tissue Treg entry. Finally, tissue Tregs extracted from non-lymphoid organs were tissue-agnostic on re-entry, without homing preference for their tissue of origin. Together these results demonstrate that the tissue-resident Treg pool in most non-lymphoid organs, other than the gut, is largely constituted by broadly self-reactive Tregs, characterised by transient multi-tissue migration and a common residency program.

immunology↗

bioRxiv2019

Chromosome-wide distribution and characterization of intersubspecific meiotic noncrossovers in mice

During meiosis, the recombination-initiating DNA double-strand breaks (DSBs) are repaired by crossovers or noncrossovers (gene conversions). While crossovers are easily detectable, the noncrossover identification is hampered by the small size of their converted tracts and the necessity of sequence polymorphism to detect them. We report identification and characterization of a mouse chromosome-wide set of noncrossovers by NGS sequencing of 10 mouse chromosome substitution strains. Based on 94 identified noncrossovers we determined the mean length of a conversion tract to be 32 basepairs. The spatial chromosome-wide distribution of noncrossovers and crossovers significantly differed, though both sets overlapped the known hotspots of PRDM9-directed histone methylation and DNA DSBs, thus proving their origin in the standard DSB repair pathway. A significant deficit of noncrossovers descending from asymmetric DSBs pointed to sister chromatids as an alternative template for their repair. The finding has implications for the molecular mechanism of hybrid sterility in mice.

genetics↗

bioRxiv2019

Genomic structure of Hstx2 modifier of Prdm9-dependent hybrid male sterility in mice

F1 hybrids between mouse inbred strains PWD and C57BL/6 represent the most thoroughly genetically defined model of hybrid sterility in vertebrates. Hybrid male sterility can be fully reconstituted from three components of this model, namely the Prdm9 hybrid sterility gene, intersubspecific homeology of Mus musculus musculus and Mus musculus domesticus autosomes, and the X-linked Hstx2 locus. Hstx2 modulates the extent of Prdm9-dependent meiotic arrest and harbors two additional genetic factors responsible for intersubspecific introgression-induced oligospermia (Hstx1) and reduced global meiotic recombination rate (Meir1). To facilitate positional cloning and to overcome the recombination suppression within the 4.3 Mb genomicDob interval encompassing the Hstx2 locus we designed Hstx2-CRISPR and SPO11/Cas9 transgenes aimed to induce DNA double-strand breaks specifically within the Hstx2 locus. The resulting recombinant reduced the Hstx2 locus to 2.70 Mb (Chr X:66.51-69.21 Mb). The newly defined Hstx2 still operates as the major X-linked factor of the F1 hybrid sterility, controls meiotic chromosome synapsis, and modifies meiotic recombination rate. Despite extensive further crosses, the 2.70 Mb Hstx2 interval behaved as a recombination cold spot with reduced PRDM9-mediated H3K4 hotspots and absence of DMC1-defined DNA DSB hotspots. To search for structural anomalies as a possible cause of recombination suppression we used optical mapping of the Hstx2 interval and observed high incidence of subspecies-specific structural variants along the X chromosome, with a striking copy number polymorphism of the microRNA Mir465 cluster. Finally, we analyzed the role of one of the Hstx2 candidate genes, the Fmr1 neighbor (Fmr1nb) gene in male fertility.\n\nArticle summaryEarly meiotic arrest of mouse intersubspecific hybrids depends on the interaction between the Prdm9 gene and Hybrid sterility X2 (Hstx2) locus on chromosome X. Lustyk et al. conducted high-resolution genetic and physical mapping of the Hstx2 locus, reduced it to 2.7 Mb interval within a constitutive recombination cold spot and found that the newly defined Hstx2 still operates as the X-linked hybrid sterility factor, controls meiotic chromosome synapsis, and modifies recombination rate. Optical mapping of the Hstx2 genomic region excluded inversion as a cause of recombination suppression and revealed a striking copy number polymorphism of the microRNA Mir465 cluster.

genetics↗

bioRxiv2017

Interference with Prdm9-controlled meiotic chromosome asynapsis overrides hybrid sterility in mice

The infertility of hybrids between closely related species is one of the reproductive isolation mechanisms leading to speciation. Prdm9, the only known vertebrate hybrid sterility gene causes failure of meiotic chromosome synapsis and infertility in male hybrids between mouse strains derived from two mouse subspecies. Within species Prdm9 determines the sites of programmed DNA double-strand breaks and meiotic recombination hotspots. To investigate the relation between Prdm9-controlled meiotic arrest and asynapsis, we inserted random stretches of consubspecific homology on several autosomal pairs in sterile hybrids and analyzed their ability to form synaptonemal complexes and rescue male fertility. Twenty-seven or more Mb of consubspecific homology fully restored synapsis in a given autosomal pair and we predicted that two symmetric DSBs or more per chromosome are necessary for successful meiosis. We hypothesize that impaired recombination between evolutionary diverged homologous chromosomes could function as one of the mechanisms of hybrid sterility occurring in various sexually reproducing species.

evolutionary biology↗