A5088029990- T-cell and B-cell Immunology
- Immune Cell Function and Interaction
- Biochemical and Molecular Research
- Monoclonal and Polyclonal Antibodies Research
- HIV/AIDS drug development and treatment
- Immunotherapy and Immune Responses
- Bone health and treatments
- Organophosphorus compounds synthesis
- Plant biochemistry and biosynthesis
- Synthesis and Biological Evaluation
- Ubiquitin and proteasome pathways
- Click Chemistry and Applications
- Protein Kinase Regulation and GTPase Signaling
- Cell Adhesion Molecules Research
- Chemical Synthesis and Analysis
- Retinoids in leukemia and cellular processes
- Carbohydrate Chemistry and Synthesis
- Pneumocystis jirovecii pneumonia detection and treatment
- Histone Deacetylase Inhibitors Research
- NF-κB Signaling Pathways
- Microbial Natural Products and Biosynthesis
- X-ray Diffraction in Crystallography
- Synthetic Organic Chemistry Methods
- Crystallization and Solubility Studies
- Quinazolinone synthesis and applications
University of Connecticut
2016-2025
Institute for Systems Biology
2016
University of Wisconsin–Madison
2009-2011
University of Iowa
2000-2011
Institute on Aging
2009-2011
University of Iowa Hospitals and Clinics
2005
Phosphoantigen-sensitive Vγ9Vδ2 T cells are important responders to infections and malignancy. However, the mechanisms by which phosphoantigens stimulate unclear. Here, we synthesized phosphoantigen prodrugs used them demonstrate that intracellular delivery of is required for their activity. The pivaloyloxymethyl prodrug most potent described date, with stronger stimulation from human peripheral blood greater ability induce lysis Daudi lymphoma relative previously compound,...
Butyrophilin (BTN)-3A and BTN2A1 molecules control the activation of human Vγ9Vδ2 T cells during cell receptor (TCR)-mediated sensing phosphoantigens (PAg) derived from microbes tumors. However, molecular rules governing PAg remain largely unknown. Here, we establish three mechanistic principles PAg-mediated γδ activation. First, in humans, following binding to intracellular BTN3A1-B30.2 domain, TCR triggering involves extracellular V-domain BTN3A2/BTN3A3. Moreover, localization both protein...
T cell-APC contact initiates cell activation and is maintained by the integrin LFA-1. Talin1, an LFA-1 regulator, localizes to immune synapse (IS) with unknown roles in activation. In this study, we show that talin1-deficient cells have defects contact-dependent stopping proliferation. Although did not form stable interactions APCs, transient contacts were sufficient induce signaling. contrast prior models, polarized cells, but vinculin F-actin polarization at IS was impaired. These results...
The asymmetric total syntheses of the natural products (+)- and (−)-frondosin B (+)-frondosin A are reported based on a diastereoselective cycloaddition between tetrabromocyclopropene an annulated furan to provide highly functionalized common building block. bridged bicyclic intermediate could be stereo- chemoselectively manipulated produce two structurally distinct members frondosins. Both feature regioselective palladium-coupling reactions unprecedented phosphine-mediated ether bridge...
Abstract Poliovirus receptor (PVR) ligands have gained attention as immunotherapy targets, yet their regulation remains unclear. Here, we examine the impact of PVR exposure on primary human CD8+ T cells. We used flow cytometry and Western blot analysis to quantify expression its in naïve effector cells adhesion assays enzyme-linked immunosorbent assay (ELISA) assess cell cytokine production. Stimulation with phytohemagglutinin P strongly increased DNAM-1 caused a less robust more variable...
Abstract Butyrophilin 3A1 (BTN3A1) is an integral membrane protein capable of detecting phosphoantigens, like ( E )‐4‐hydroxy‐3‐methyl‐but‐2‐enyl diphosphate (HMBPP), through its internal B30.2 domain. Detection phosphoantigens leads to interactions with butyrophilin 2A1 and the subsequent activation γδ‐T cells. Though crystallography functional assays have been crucial for determining vital residues BTN3A1/HMBPP/BTN2A1 complex, mechanism signal transduction still unclear. Here, we utilize...
Small isoprenoid diphosphates, such as (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP), are ligands of the internal domain BTN3A1. Ligand binding in target cells promotes activation Vγ9Vδ2 T cells. We demonstrate by small-angle X-ray scattering (SAXS) that HMBPP to BTN3A1 induces a conformational change position B30.2 relative juxtamembrane (JM) region. To better understand molecular details this rearrangement, NMR spectroscopy was used discover JM region interacts with HMBPP,...
Studies of aryl phosphonate derivatives a butyrophilin 3A1 ligand have resulted in identification potent stimulant Vγ9 Vδ2 T cells. This compound, mixed ester bearing one pivaloyloxymethyl substituent and 1-naphthyl displayed an EC50 0.79 nM as cell proliferation, 9.0 assay designed to measure interferon gamma production. In both assays, this is the most prodrug yet reported, thus it should be valuable tool for studies function. Furthermore, aryl/acyloxyalkyl esters may represent new class...
Small organophosphorus compounds stimulate Vγ9 Vδ2 T cells if they serve as ligands of butyrophilin 3A1. Because the most potent natural ligand is ( E)-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP), which last intermediate in bacterial biosynthesis isoprenoids that not found mammalian metabolism, activation these represents an important component immune response to infections. To identify may have greater plasma stability, and clinical potential, we prepared a set aryl phosphonamidate...
Abstract Vγ9Vδ2 effector T cells lyse in response to phosphorus-containing small molecules, providing primates a unique route remove infected or malignant cells. Yet, the triggering mechanisms remain ill defined. We examined lysis mediated by human naturally occurring (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP) synthetic cell-permeable prodrug, bis (pivaloyloxymethyl) phosphonate. CD27+/CD45RA− Th1-like killed K562 target through mechanism that could be enhanced either compound TCR...
Inhibitors of isoprenoid synthesis are widely used for treatment human diseases, including hypercholesterolemia and osteoporosis, they have the potential to be useful cancer. Statin drugs inhibit enzyme HMG-CoA reductase, whereas nitrogenous bisphosphonates more recently been shown farnesyl disphosphate synthase. In addition, our laboratory has developed several potent specific bisphosphonate inhibitors geranylgeranyl diphosphate synthase, digeranyl bisphosphonate. Because all three enzymes...
The T cell migration stop signal is a central step in activation and inflammation; however, its regulatory mechanisms remain largely unknown. Using live-cell, imaging-based, high-throughput screen, we identified the PG, PGE(2), as antagonist. Src kinase inhibitors, microtubule PGE(2) prevented signal, impaired cell-APC conjugation proliferation induced by primary human allogeneic dendritic cells. However, inhibition, but not or TCR-induced ZAP-70 signaling, demonstrating that antagonists can...