Biology subjects

Dikovskaya, D.

Publications and source records attributed to Dikovskaya, D..

4 recordsLinked to original sources

bioRxiv2025

Intraepithelial lymphocytes exhibit selective immunity to intestinal pathogens

Intraepithelial lymphocytes (IEL) are abundant, tissue-resident T cells critical for intestinal immune surveillance, yet their precise roles have remained elusive due to the lack of models enabling their selective genetic ablation. Here, we report the generation of Gzmb-Cre knock-in mice, that when crossed with inducible Diphtheria toxin receptor mice, allows targeted and inducible ablation of IELs without perturbing peripheral immunity. Using this model (referred to as IELiDTR), we demonstrate that IELs are dispensable for intestinal homeostasis, including epithelial architecture, barrier function and microbial composition. However, loss of IELs led to increased intestinal infection by Salmonella Typhimurium and Cryptosporidium parvum, but did not affect responses to Listeria monocytogenes infection or DSS colitis. Interestingly, IEL deficiency reduced fecundity of the intestinal nematode, Heligmosomoides polygyrus, despite unaltered worm burden, suggesting a permissive role in helminth colonization. These findings position IELs as evolutionary-tuned sentinels against co-evolved pathogens that can cause lethal diarrheal diseases, and establish the IELiDTR mouse as a vital genetic tool for dissecting IEL function in host-pathogen interactions in vivo.

immunology↗

bioRxiv2024

Regulation of Leucine-Rich Repeat Kinase 2 by inflammation and IL-4

Mutations in Leucine-Rich Repeat protein Kinase 2 (LRRK2) are associated with Parkinsons Disease (PD) and Crohns Disease (CD), but the regulation of LRRK2 during inflammation remains relatively unexplored. Here we developed a flow cytometry-based assay to assess LRRK2 activity in individual cells and created an EGFP-Lrrk2-knock-in reporter mouse to analyse cell-specific LRRK2 expression. Using these tools, we catalogued LRRK2 levels and activity in splenic and intestinal immune cells. Inflammation increased LRRK2 expression and activity in B-cells, immature neutrophils and immature monocytes, but decreased these in dendritic cells and eosinophils. In mature neutrophils, inflammation stimulated activity but reduced LRRK2 expression. A kinase-activating PD-associated LRRK2-R1441C mutation exacerbated inflammation-induced activation of LRRK2 specifically in monocytes and macrophages without affecting LRRK2 levels. Finally, we identified IL-4 as a novel factor that upregulated LRRK2 expression and activity in B-cells, replicating inflammatory effects observed in vivo. Our findings provide valuable new insights into the regulation of the LRRK2 pathway in immune cells, crucial for understanding LRRK2 and its therapeutic potential in inflammatory diseases such as CD.

immunology↗

bioRxiv2024

Leucine Rich Repeat Kinase 2 is not required for lysozyme expression in intestinal Paneth cells

Genetic variants in Leucine-rich Repeat Kinase 2 (LRRK2) gene have been linked to Parkinsons disease (PD) and are also associated with inflammatory bowel diseases (IBD), specifically Crohns disease (CD), a transmural inflammation that can affect the entire length of the gastrointestinal tract and is commonly seen in the ileum1. In ileal CD, defects in specialized intestinal epithelial cells known as Paneth cells are believed to drive disease pathogenesis2,3. Paneth cells contribute to mucosal defense by secreting antimicrobial peptides including lysozyme and to the maintenance of intestinal stem cells by secreting growth factors. A previous article published by Zhang et al4 in Nature Immunology identified a key role for LRRK2 in selective sorting and secretion of lysozyme in Paneth cells. However, after extended analyses, we find that LRRK2 is not required for lysozyme expression in the murine gut and is not expressed in either murine or human Paneth cells.

physiology↗

bioRxiv2021

Opposing roles of Granzymes A and B in the immune response to intestinal infection

Intestinal intraepithelial T lymphocytes (IEL) constitutively express high amounts of the cytotoxic proteases Granzymes (Gzm) A and B and are therefore thought to protect the intestinal epithelium against infection by killing infected epithelial cells. However, the role of IEL granzymes in a protective immune response has yet to be demonstrated. We show that GzmA and GzmB are required to protect mice against oral, but not intravenous, infection with Salmonella enterica serovar Typhimurium, consistent with an intestine-specific role. IEL-intrinsic granzymes mediate the protective effects by controlling intracellular bacterial growth and aiding in cell-intrinsic pyroptotic cell death of epithelial cells. Surprisingly, we found that both granzymes play non- redundant roles. GzmB-/- mice carried significantly lower burdens of Salmonella, as predominant GzmA-mediated cell death effectively reduced bacterial translocation across the intestinal barrier. Conversely, in GzmA-/-mice, GzmB-driven apoptosis favored luminal Salmonella growth by providing nutrients, while still reducing translocation across the epithelial barrier. Together, the concerted actions of both GzmA and GzmB balance cell death mechanisms at the intestinal epithelium to provide optimal control that Salmonella cannot subvert. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=137 SRC="FIGDIR/small/467595v3_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@2b2c9corg.highwire.dtl.DTLVardef@7de81eorg.highwire.dtl.DTLVardef@1209d2org.highwire.dtl.DTLVardef@42dffb_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗