Biology subjects

Vandereyken, M.

Publications and source records attributed to Vandereyken, M..

5 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↗

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↗

bioRxiv2021

Tissue environment, not ontogeny, defines intestinal intraepithelial T lymphocytes

Tissue-resident intestinal intraepithelial T lymphocytes (T-IEL) patrol the gut and have important roles in regulating intestinal homeostasis. T-IEL include both induced T-IEL, derived from systemic antigen-experienced lymphocytes, and natural IEL, which are developmentally targeted to the intestine. While the processes driving T-IEL development have been elucidated, the precise roles of the different subsets and the processes driving activation and regulation of these cells remain unclear. To gain functional insights into these enigmatic cells, we used high-resolution, quantitative mass spectrometry to investigate the proteomic landscape of the main T-IEL populations in the gut. Comparing the proteomes of induced T-IEL and natural T-IEL subsets, with naive CD8+ T cells from lymph nodes exposes the dominant effect of the gut environment over ontogeny on T-IEL phenotypes. Analyses of protein copy numbers of >7000 proteins in T-IEL reveal skewing of the cell surface repertoire towards epithelial interactions and checkpoint receptors; strong suppression of the metabolic machinery indicating a high energy barrier to functional activation; and changes in T cell antigen receptor signalling pathways reminiscent of chronically activated T cells. These novel findings illustrate how multiple input signals need to be integrated to regulate T-IEL function.

immunology↗

bioRxiv2020

Comprehensive proteomics analyses identify PIM kinases as key regulators of IL-15 driven activation of intestinal intraepithelial lymphocytes

Intestinal intraepithelial lymphocytes (IEL) are an abundant population of tissue-resident T cells that protect the gut from pathogens and maintain intestinal homeostasis. The cytokine IL-15 is transpresented by epithelial cells to IEL in complex with the IL-15 receptor chain (IL-15R). It plays essential roles both in maintaining IEL homeostasis, and in inducing IEL activation in response to epithelial stress. IL-15 overexpression also drives the gluten-induced enteropathy Coeliac disease, through cytotoxic activation of IEL. In order to better understand how IL-15 directly regulates both homeostatic and inflammatory functions of IEL, we set up quantitative proteomics of IL-15/R stimulated IEL. We reveal that high IL-15/R stimulation licenses cell cycle activation, upregulates the biosynthetic machinery in IEL, increases mitochondrial respiratory capacity and induces expression of cell surface immune receptors and adhesion proteins that potentially drive IEL activation. We find that high IL-15/R selectively upregulated the Ser/Thr kinases PIM1 and PIM2 and demonstrate that PIM1/2 are essential for IEL to proliferate, grow, and upregulate Granzyme B in response to high IL-15. Significantly, IEL from Coeliac disease patients express high levels of PIM kinases. These unexpected findings reveal PIM kinases to be key determinants of IEL responses to elevated levels of IL-15.

immunology↗

bioRxiv2018

Loss of Adenomatous polyposis coli function renders intestinal epithelial cells resistant to the cytokine IL-22

Interleukin-22 (IL-22) is critical in maintaining homeostasis in the intestine by regulating the balance between pathogenic and commensal bacteria. IL-22 also promotes wound healing and tissue regeneration, which can support the growth of colorectal tumours. Mutations in the tumour suppressor Adenomatous Polyposis Coli gene (Apc) cause intestinal tumorigenesis and are a major driver of familial colorectal cancers. To understand the role of IL-22 in APC-mediated tumorigenesis, we analysed IL-22 signalling in wild-type (WT) and APC-mutant cells in murine small intestinal epithelial organoids and in mice. In WT epithelia, antimicrobial defence, mucus production, and cellular stress response pathways were most strongly upregulated by IL-22. Surprisingly, we found that although IL-22 activated STAT3 in APC-mutant cells, STAT3 target genes were not effectively induced. Our analyses revealed that ApcMin/Min cells were resistant to IL-22 due to reduced expression of the IL-22 receptor, and increased expression of inhibitors of STAT3, including histone deacetylases. We further show that IL-22 induced expression of nitric oxide synthase in WT epithelial cells and corresponding DNA damage. These findings suggest that IL-22 does not promotes tumour formation by driving the proliferation of transformed intestinal epithelial cells. Rather, IL-22 increases genetic instability thereby accelerating transition from heterozygosity (ApcMin/+) to homozygosity (ApcMin/Min) to drive tumour progression.

immunology↗