Publications by authors named "Dirk Zajonc"
Article Synopsis
- Costimulatory receptors like 4-1BB (CD137) on immune cells are promising targets for immunotherapy, as they can boost protective immune responses and enhance the functions of immune cells such as T cells and NK cells.
- Preclinical studies show that activating 4-1BB can improve tumor immunity and viral defense, while potentially offering benefits in managing autoimmunity through its influence on regulatory T cells.
- Clinical trials have seen mixed results with human antibodies targeting 4-1BB, prompting the development of new antibody constructs aimed at improving effectiveness and selectivity in treating cancer and other conditions.
Article Synopsis
- * In healthy individuals, ApoB-reactive CD4 T cells generally function as regulatory T cells with anti-inflammatory properties, but can shift to a pro-inflammatory, atherogenic role under certain conditions.
- * A study involving the vaccination of mice with an ApoB peptide led to the identification of distinct P6 T cell clones, showing a mix of both regulatory and proatherogenic characteristics, suggesting that vaccination can alter T cell responses to ApoB and may help in understanding cardiovascular disease mechanisms.
Article Synopsis
- T cell immune recognition begins when T cell receptors (TCRs) bind to peptide-MHC complexes, which are influenced by MHC polymorphism.
- MHC Class I molecules typically present peptides that are 8-11 amino acids long, with TCRs docking at a specific orientation, but longer peptides can bind in alternative configurations.
- New research indicates that unconventional peptide presentation, involving structural changes in MHC or the peptides themselves, can affect the immune response from both T cells and Natural Killer (NK) cells.
Article Synopsis
- - Targeting CD8 T cells to specific tumor mutations may enhance cancer treatment, especially when these mutations serve as potential tumor antigens, but their effectiveness is limited due to low affinity for common HLA class I alleles.
- - The study introduces a method to analyze proteasome-generated spliced peptides, which helps identify mutated spliced epitopes that tightly bind to dominant HLA-I alleles, making them suitable for large-scale cancer immunotherapy.
- - A successful example from this method highlighted the KRAS G12V mutation, showing that the corresponding spliced epitope is efficiently produced and presented by prevalent HLA class I molecules, suggesting its potential role in T cell therapy.
Article Synopsis
- * Recent findings show that while most iNKT cell agonists like α-GalCer induce strong immunity, β-ManCer, a β-linked glycolipid, can also promote antitumor responses but through different mechanisms.
- * The study reveals that antibodies designed to detect CD1d-α-GalCer complexes can also recognize β-ManCer-CD1d complexes, suggesting a structural similarity in their interaction despite differences in carbohydrate structure, prompting a reevaluation of data related to these antibodies.
Article Synopsis
- Invariant natural killer T (iNKT) cells recognize specific lipids via the CD1d molecule, which can interact with both activating and non-activating lipids, like sphingomyelin.
- Researchers found that a lack of the enzyme acid sphingomyelinase (ASM), which breaks down sphingomyelin, leads to reduced iNKT cell levels and impaired immune responses in both mice and humans with Niemann-Pick disease.
- Administering ASM can enhance antigen presentation and restore iNKT cell levels in ASM-deficient mice, highlighting the importance of sphingolipid metabolism in immune function.
Article Synopsis
- * Researchers Spangler developed a method to select antibodies specifically targeting the IL-4Rα/γ heterodimer in its active signaling form, resulting in a unique "stapler" antibody.
- * This innovative technique has the potential to be applied to other receptor types, enabling signaling in scenarios where natural ligands are not present.
Article Synopsis
- Type I natural killer T (NKT) cells respond swiftly to α-GalCer presented by CD1d, affecting immune response through cytokine production.
- Researchers developed α-galactosylsphingamides (αGSAs) as potential adjuvants, but found they are weak antigens despite having high T-cell receptor-binding affinity.
- The study revealed that a molecular switch in murine CD1d, involving a hydrogen bond with Tyr-73, regulates NKT cell activation by αGSAs, highlighting the significance of acyl chain length on immune response modulation.
Article Synopsis
- * Previous studies have created several anti-CD1d antibodies to block the interaction between CD1d and T-cell receptors, allowing researchers to explore NKT cell activation, but limitations exist depending on the specificity of these antibodies.
- * The authors present the crystal structure of a common anti-mouse CD1d antibody, 1B1, highlighting its binding characteristics and limitations when evaluating NKT cell activation, especially for antigens that do not conform to typical structural rules.
Article Synopsis
- Human cytomegalovirus (HCMV) is a herpesvirus that can persist in the body for life by evading the immune system, using molecules like glycoprotein UL144 to manipulate immune responses.
- The UL144 protein mimics the HVEM receptor but only interacts with BTLA to inhibit T-cell activation, and researchers detailed how this happens through the crystal structure of the UL144-BTLA complex.
- By via structure-guided mutagenesis, a specific mutant of BTLA was found that can interfere with HVEM but still allows binding with UL144, providing insights into the differences between the two proteins and suggesting potential for developing better immune inhibitors.
Article Synopsis
- * They achieved this by attaching antigenic peptides to a weaker agonist called α-galactosylphytosphingosine (α-GalPhs), which helps in safely stimulating NKT cells.
- * This method not only proved effective in activating human T cells in lab settings but also showed promising anti-tumor effects in mice, suggesting a new approach for improving immunity against viruses and tumors.
Article Synopsis
- Leukocyte adhesion is dependent on the activation of β-integrins, which need to shift from a bent-closed conformation to an extended-high affinity form to effectively bind to intercellular adhesion molecules (ICAMs).
- Researchers developed a technique called Super-STORM that combines super-resolution microscopy with molecular modeling to visualize activated integrins on primary human neutrophils with high precision.
- When neutrophils arrest, activated integrins cluster in a specific face-to-face orientation, and blocking their binding to ICAMs changes this orientation, suggesting that this pattern is crucial for effective immune responses.
Invariant natural killer T-cells (iNKT) are a glycolipid-responsive subset of T-lymphocytes that fulfill a pivotal role in the immune system. The archetypical synthetic glycolipid, α-galactosylceramide (α-GalCer), whose molecular framework is inspired by a group of amphiphilic natural products, remains the most studied antigen for iNKT-cells. Nonetheless, the potential of α-GalCer as an immunostimulating agent is compromised by the fact that this glycolipid elicits simultaneous secretion of Th1- and Th2-cytokines.
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- The interaction between mouse 4-1BB and 4-1BBL is crucial for T-cell activation, but differences from humans may affect this process.
- Researchers determined the crystal structure of mouse 4-1BBL and its complex with 4-1BB, revealing that mouse 4-1BBL forms a unique disulfide-linked dimer, unlike typical trimeric structures of similar proteins.
- The study identified key amino acids responsible for this dimerization and showed that when 4-1BB binds, the structure of 4-1BBL changes, enhancing interaction efficiency; significant differences between mouse and human complexes explain their lack of cross-reactivity.
Article Synopsis
- The study found that normal mice have αβ T cells that specifically recognize self-glycerophospholipids, like phosphatidic acid (PA), in a way that is restricted by CD1d without cross-reacting with iNKT-cell ligands.
- Glycerophospholipids, such as PA, can effectively compete for binding to CD1d, potentially influencing immune balance between lipid-reactive T cell subsets, which has significant health implications.
Human cytomegalovirus (HCMV) is a ubiquitous human herpesvirus. While HCMV infection is generally asymptomatic in the immunocompetent, it can have devastating consequences in those with compromised or underdeveloped immune systems, including transplant recipients and neonates. Galectins are a widely expressed protein family that have been demonstrated to modulate both antiviral immunity and regulate direct host-virus interactions.
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- Human 4-1BB (h4-1BB) is a receptor that, along with its ligand h4-1BBL, plays a key role in activating T lymphocytes, crucial for cancer immunotherapy.
- Researchers determined the crystal structures of h4-1BBL and its complex with both the wild type (WT) h4-1BB and a mutant form, revealing a unique bell shape for h4-1BBL rather than the previously thought propeller shape.
- The study found that h4-1BB binds primarily to one protomer of h4-1BBL and forms disulfide-linked dimers, which may enhance signaling through a cross-linked network of receptor-ligand
Article Synopsis
- Vaccinia virus A14 is a key protein in the smallpox vaccine and a target for antibodies, but its role in immunity against related viruses is not well understood.
- In a study, researchers created 22 monoclonal antibodies (mAbs) to analyze their bindings, finding that most targeted a specific area of the protein, while none attached directly to the virus structure.
- Some mAbs showed potential in neutralizing the virus when combined with complement and offered protection to mice infected with the virus, suggesting that anti-A14 antibodies may aid immunity through a different mechanism rather than direct binding to the virus.
Article Synopsis
- Integrin-based therapies are important in treating inflammation but their general use is limited due to their role in host defense.
- The novel monoclonal antibody anti-M7 effectively blocks the pro-inflammatory interaction between the integrin Mac-1 and its ligand CD40L without disrupting other critical integrin functions.
- Unlike traditional anti-Mac-1 therapies that can worsen conditions like sepsis, anti-M7 offers a specific and protective approach to managing inflammation by selectively reducing leukocyte recruitment.
Article Synopsis
- 4-1BB (CD137) is a member of the TNF receptor superfamily that, when bound to its ligand 4-1BBL, undergoes trimerization to trigger immune responses.
- The study revealed the crystal structure of mouse 4-1BB, displaying unique arrangements of cysteine-rich domains compared to other TNFRSFs, and identified key glycosylation sites that facilitate binding to galectin-9 (Gal-9).
- The research suggests that while 4-1BBL forms a covalent dimer, its interaction with Gal-9 is crucial for aggregating m4-1BB monomers, which is essential for effective signaling in the immune system.
Article Synopsis
- Vaccinia virus envelope protein D8, a key molecule in smallpox vaccine immunology, binds to chondroitin sulfate and is targeted by neutralizing antibodies, yet its atomic-level interaction with human antibodies was previously unexplored.
- Researchers identified and analyzed three specific human antibodies against D8, revealing their high binding affinity and their ability to block D8's interaction with different forms of chondroitin sulfate.
- The study suggests potential for engineering D8 to enhance its binding specificity, with implications for developing a diagnostic tool for detecting structures linked to ovarian cancer due to D8's binding properties to kidney glomeruli expressing chondroitin sulfate.
Stimulation of several TNF receptor family proteins has been shown to dampen inflammatory disease in murine models through augmenting the number and/or activity of regulatory T cells (Tregs). We recently found that one molecule, 4-1BB, used binding to Galectin-9 to exert its immunosuppressive effects and drive expansion of CD8Foxp3 Tregs. We now show that ligation of another TNFR family molecule, DR3, which has previously been found to strongly expand CD4Foxp3 Tregs and suppress inflammation, also requires Galectin-9.
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- Qa-1 is a special protein that presents certain peptides to immune cells, helping them monitor and regulate immune responses, especially against activated T cells.
- Four types of Qa-1 exist (Qa-1a-d), which have similar structures but differ in some amino acids that can influence how peptides bind and are recognized by T cell receptors (TCRs).
- The study focused on the structure of Qa-1a with a specific peptide, finding key differences in the binding pocket that may lead to different T cell interactions and immune responses compared to Qa-1b.
Article Synopsis
- Invariant Natural Killer T-cells (iNKT-cells) are promising targets for enhancing immune responses, especially when stimulated by CD1d with a compound called KRN7000.
- This study presents a new way to modify the side chain of KRN7000 quickly, using a method called amidation on a specific precursor compound.
- The new derivatives, called α-galactosylsphingamides, were tested for their ability to stimulate iNKT-cells, but while they maintained some binding ability, they showed reduced effectiveness as antigens.