Biology subjects

Edelblum, K. L.

Publications and source records attributed to Edelblum, K. L..

6 recordsLinked to original sources

bioRxiv2026

Epithelial and γδ T cell CD47 have complementary yet distinct roles in regulating γδ intraepithelial lymphocyte migration

Intraepithelial lymphocytes expressing the {gamma}{delta} T cell receptor ({gamma}{delta} IEL) continuously survey the intestinal epithelium to promote mucosal host defense. Although {gamma}{delta} IELs migrate in and out of the lateral intercellular space (LIS) between adjacent enterocytes, the molecular mechanisms governing their migratory behavior are incompletely understood. Based on the known role of CD47, or integrin associated protein (IAP), in mediating neutrophil transepithelial migration, we investigated whether CD47 expression reflects a conserved mechanism regulating {gamma}{delta} IEL surveillance behavior. Here, we report that conditional CD47 deletion on intestinal epithelial cells or {gamma}{delta} T cells had no effect on IEL composition. Using intravital imaging, we identified complementary roles for CD47 on {gamma}{delta} IELs and epithelial cells, with epithelial CD47 restricting {gamma}{delta} IEL motility and {gamma}{delta} T-cell-derived CD47 promoting cell migration. Further investigation revealed that both CD47 and CD18 contribute to {gamma}{delta} IEL surveillance behavior, although CD47 regulates {gamma}{delta} IEL migration in a CD18-independent manner.

immunology↗

bioRxiv2025

Microbiota promote enhanced CD39 expression in γδ intraepithelial lymphocytes through the activation of TCR and IL-15 signaling

Intraepithelial lymphocytes expressing the {gamma}{delta} T cell receptor ({gamma}{delta} IEL) provide continuous surveillance of the intestinal epithelium. We report that mice harboring a microbiota-specific hyperproliferative {gamma}{delta} IEL ({gamma}{delta}HYP) phenotype also upregulate the expression of the ectonucleotidase CD39, a marker of regulatory {gamma}{delta} T cells. Enhanced TCR and IL-15 signaling correlates with a progression from a naive-like CD39neg {gamma}{delta} IEL to a more mature, tissue-adapted CD39hi IEL population. We found that TCR{gamma}{delta} activation drives CD122-mediated CD39 upregulation on {gamma}{delta}HYP IELs and increased mucosal IL-15 further amplifies CD39 expression in these cells. Further investigation revealed that CD39 induction requires sustained exposure to the {gamma}{delta}HYP-associated microbiota. Moreover, CD39hi {gamma}{delta} IELs exhibit a reduced capacity to produce pro-inflammatory cytokine, which may explain the lack of histopathology in {gamma}{delta}HYP mice. Overall, our study identifies a previously unappreciated mechanism by which an altered microbiota amplifies CD39 expression on {gamma}{delta}HYP IELs, leading to the expansion of {gamma}{delta} IELs with regulatory potential.

immunology↗

bioRxiv2024

Type I interferon induces TCR-dependent and -independent antimicrobial responses in γδ intraepithelial lymphocytes

Intraepithelial lymphocytes (IEL) expressing the {gamma}{delta} T cell receptor (TCR) survey the intestinal epithelium to limit the invasion of microbial pathogens. The production of type I interferon (IFN) is a central component of an antiviral immune response, yet how these pro-inflammatory cytokines contribute to {gamma}{delta} IEL effector function remains unclear. Based on the unique activation status of IELs, and their ability to bridge innate and adaptive immunity, we investigated the extent to which type I IFN signaling modulates {gamma}{delta} IEL function. Using an ex vivo culture model, we find that type I IFN alone is unable to drive IFN{gamma} production, yet low level TCR activation synergizes with type I IFN to induce IFN{gamma} production in murine {gamma}{delta} IELs. Further investigation into the underlying molecular mechanisms of co-stimulation revealed that TCR{gamma}{delta}-mediated activation of NFAT and JNK is required for type I IFN to promote IFN{gamma} expression in a STAT4- dependent manner. Whereas type I IFN rapidly upregulates antiviral gene expression independent of a basal TCR{gamma}{delta} signal, neither tonic TCR triggering nor the presence of a TCR agonist was sufficient to elicit type I IFN-induced IFN{gamma} production in vivo. However, bypassing proximal TCR signaling events synergized with IFNAR/STAT4 activation to induce {gamma}{delta} IEL IFN{gamma} production. These findings indicate that {gamma}{delta} IELs contribute to host defense in response to type I IFN by mounting a rapid antimicrobial response independent of TCR{gamma}{delta} signaling, and under permissive conditions, produce IFN{gamma} in a TCR-dependent manner.

immunology↗

bioRxiv2023

Dysregulation of γδ intraepithelial lymphocytes precedes Crohn's disease-like ileitis

Intraepithelial lymphocytes expressing the {gamma}{delta} T cell receptor ({gamma}{delta} IELs) provide immunosurveillance of the intestinal barrier. Interestingly, {gamma}{delta} IEL number is reduced in patients with active Crohns disease (CD). Here, we report an underappreciated role for {gamma}{delta} IELs in maintaining mucosal tolerance during the onset and progression of CD-like ileitis using the TNF{Delta}ARE/+ mouse model. Decreased epithelial HNF4G/BTNL expression is followed by a loss of ileal {gamma}{delta} IELs and impaired barrier surveillance prior to the histological onset of disease. A reduction of immunoregulatory CD39+ {gamma}{delta} IELs coincides with the influx of immature, peripheral CD39- {gamma}{delta} T cells into the epithelium leading to an expansion of induced IELs, while an earlier depletion of {gamma}{delta} IELs correlates with accelerated onset of ileal inflammation. Our findings identify multiple layers of {gamma}{delta} IEL dysregulation prior to ileitis development indicating that the loss of tissue-resident immunoregulatory {gamma}{delta} IELs may contribute to the initiation of ileal CD.

immunology↗

bioRxiv2021

A transmissible γδ intraepithelial lymphocyte hyperproliferative phenotype is associated with the intestinal microbiota and confers protection against acute infection.

Intraepithelial lymphocytes expressing the {gamma}{delta} T cell receptor ({gamma}{delta} IELs) serve as a first line of defense against luminal microbes. Although the presence of an intact microbiota is dispensable for {gamma}{delta} IEL development, several microbial factors contribute to the maintenance of this sentinel population. However, whether specific commensals influence population of the {gamma}{delta} IEL compartment under homeostatic conditions has yet to be determined. We identified a novel {gamma}{delta} IEL hyperproliferative phenotype that arises early in life and is characterized by expansion of multiple V{gamma} subsets. Horizontal transfer of this hyperproliferative phenotype to mice harboring a phenotypically normal {gamma}{delta} IEL compartment was prevented following antibiotic treatment, thus demonstrating that the microbiota is both necessary and sufficient for the observed increase in {gamma}{delta} IELs. Further, we identified a group of unique gut bacteria represented by 5 amplicon sequence variants (ASV) which are strongly associated with {gamma}{delta} IEL expansion. Using intravital microscopy, we find that hyperproliferative {gamma}{delta} IELs also exhibit increased migratory behavior leading to enhanced protection against bacterial infection. These findings reveal that transfer of a specific group of commensals can regulate {gamma}{delta} IEL homeostasis and immune surveillance, which may provide a novel means to reinforce the epithelial barrier.

immunology↗

bioRxiv2021

γδ intraepithelial lymphocytes facilitate pathological epithelial cell shedding via CD103-mediated granzyme release.

Excessive shedding of enterocytes into the intestinal lumen is observed in inflammatory bowel disease and is correlated with disease relapse. However, the mechanisms underlying this phenomenon remain unclear. Intraepithelial lymphocytes (IEL) expressing the {gamma}{delta} T-cell receptor (TCR) provide surveillance of the intestinal mucosa at steady-state, which is regulated, in part, by CD103. Intravital microscopy of lipopolysaccharide (LPS)-treated mice revealed that {gamma}{delta} IELs make extended contact with shedding enterocytes. These prolonged interactions require CD103 engagement by E-cadherin, as CD103 blockade significantly reduces LPS-induced shedding. Furthermore, we find that granzymes A and B, but not perforin, are required for cell shedding, and that these granzymes are released by {gamma}{delta} IELs both constitutively and following CD103/E-cadherin ligation. These findings indicate that extracellular granzyme facilitates shedding, likely through cleavage of extracellular matrix proteins. Our results uncover a previously unrecognized role for {gamma}{delta} IELs in facilitating pathological cell shedding in a CD103- and granzyme-dependent manner.

immunology↗