A5033682714- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- Immunotherapy and Immune Responses
- CAR-T cell therapy research
- SARS-CoV-2 and COVID-19 Research
- Cancer Immunotherapy and Biomarkers
- COVID-19 Clinical Research Studies
- Monoclonal and Polyclonal Antibodies Research
- vaccines and immunoinformatics approaches
- Immune Response and Inflammation
- Influenza Virus Research Studies
- NF-κB Signaling Pathways
- Long-Term Effects of COVID-19
- HIV Research and Treatment
- Neuroblastoma Research and Treatments
- Viral gastroenteritis research and epidemiology
- Cytomegalovirus and herpesvirus research
- Glycosylation and Glycoproteins Research
- Immune responses and vaccinations
- Peptidase Inhibition and Analysis
- interferon and immune responses
- CRISPR and Genetic Engineering
- IL-33, ST2, and ILC Pathways
- Respiratory viral infections research
Cardiff University
2017-2025
Australian Regenerative Medicine Institute
2020-2024
Monash University
2020-2024
Institute of Infection and Immunity
2017-2020
Australian Research Council
2020
Abstract The closely related inhibitory killer-cell immunoglobulin-like receptors (KIR), KIR2DL2 and KIR2DL3, regulate the activation of natural killer cells (NK) by interacting with human leukocyte antigen-C1 (HLA-C1) group molecules. KIR2DL2, KIR2DL3 HLA-C1 are highly polymorphic, this variation being associated differences in onset progression some diseases. However, molecular bases underlying these associations remain unresolved. Here, we determined crystal structures complex HLA-C*07:02...
<title>Abstract</title> <bold>Background</bold> Fungi have been a rich source of pharmaceuticals such as antibiotics, immunosuppressants, and cholesterol-lowering drugs; however, their therapeutic potential remains largely untapped due to difficulties in culturing elucidating the genetic basis beneficial traits. contain 'cryptic' genes that are expressed under certain, often obscure, growth conditions can produce complex compounds difficult synthesize economically. Developments genome...
CD4+ T cells recognize a broad range of peptide epitopes severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which contribute to immune memory and limit COVID-19 disease. We demonstrate that the immunogenicity SARS-CoV-2 peptides, in context model allotype HLA-DR1, does not correlate with their binding affinity HLA heterodimer. Analyzing six epitopes, some very low affinity, we solve X-ray crystallographic structures each bound HLA-DR1. Further structural definitions reveal precise...
T-cell immunity is controlled by receptor (TCR) binding to peptide major histocompatibility complexes (pMHCs). The nature of the interaction between these two proteins has been subject many investigations because its central role in against pathogens, cancer, autoimmunity, and during organ transplant rejection. Crystal structures comparing unbound pMHC-bound TCRs have revealed flexibility at interface, particularly from perspective TCR. However, crystal represent only a snapshot protein...
Micropolymorphisms within human leukocyte antigen (HLA) class I molecules can change the architecture of peptide-binding cleft, leading to differences in peptide presentation and T cell recognition. The impact such HLA variation on natural killer (NK) recognition remains unclear. Given differential association HLA-B*57:01 HLA-B*57:03 with control HIV, these HLA-B57 allomorphs by immunoglobulin-like receptor (KIR) 3DL1 was compared. Despite differing only two polymorphic residues, both buried...
Abstract Immune checkpoint inhibitors (antibodies that block the T cell co‐inhibitory receptors PD‐1/PD‐L1 or CTLA‐4) have revolutionized treatment of some forms cancer. Importantly, combination approaches using drugs target both pathways been shown to boost efficacy such treatments. Subsequently, several other inhibitory identified for development novel immune inhibitors. Included in this list is receptor lymphocyte activation gene‐3 (LAG‐3), which upregulated on cells extracted from tumor...
Abstract HLA class I molecules that represent ligands for the inhibitory killer cell Ig-like receptor (KIR) 3DL1 found on NK cells are categorically defined as those HLA-A and HLA-B allotypes containing Bw4 motif, yet KIR3DL1 demonstrates hierarchical recognition of these HLA-Bw4 ligands. To better understand molecular basis underpinning differential recognition, HLA-ABw4 family were investigated. Transfected human 721.221 expressing HLA-A*32:01 strongly inhibited primary KIR3DL1+ cells,...
T cell recognition of peptides presented by human leukocyte antigens (HLAs) is mediated the highly variable receptor (TCR). Despite this built-in TCR variability, individuals can mount immune responses against viral epitopes using identical or related TCRs expressed on CD8+ cells. Characterization these has extended our understanding molecular mechanisms that govern peptide-HLA. However, few examples exist for CD4+ Here, we investigate to internal proteins influenza A virus correlate with...
Immuno-oncology approaches that utilize T cell receptors (TCRs) are becoming highly attractive because of their potential to target virtually all cellular proteins, including cancer-specific epitopes, via the recognition peptide-human leukocyte antigen (pHLA) complexes presented at surface. However, natural TCRs generally recognize cancer-derived pHLAs with very weak affinities, efforts have been made enhance binding strength, in some cases by several million-fold. In this study, we...
Abstract The intracellular proteome of virtually every nucleated cell in the body is continuously presented at surface via human leukocyte antigen class I (HLA-I) processing pathway. This pathway classically involves proteasomal degradation proteins into short peptides that can be by HLA-I molecules for interrogation T-cell receptors (TCRs) expressed on CD8+ T cells. During initiation a immune response, TCR acts as cell’s primary sensor, using flexible loops to mould around pHLA-I molecule...
CD4
The oncofoetal antigen 5T4 is a promising T cell target in the context of colorectal cancer, as demonstrated by recent clinical study where 5T4-specific responses, induced vaccination or cyclophosphamide, were associated with significantly prolonged survival patients metastatic disease. Whilst Th1-type (IFN-γ+) responses specific to 5T4, and other antigens, are often readily detectable early stage CRC healthy donors, their activity suppressed cancer progresses CD4+CD25hiFoxp3+ regulatory...
Human CD8+ cytotoxic T lymphocytes (CTLs) are known to play an important role in tumor control. In order carry out this function, the cell surface-expressed T-cell receptor (TCR) must functionally recognize human leukocyte antigen (HLA)-restricted tumor-derived peptides (pHLA). However, we and others have shown that most TCRs bind sub-optimally antigens. Uncovering molecular mechanisms define poor recognition could aid development of new targeted therapies circumnavigate these shortcomings....
Human CD8+ cytotoxic T lymphocytes (CTLs) are known to play an important role in tumor control. In order carry out this function, the cell surface-expressed T-cell receptor (TCR) must functionally recognize human leukocyte antigen (HLA)-restricted tumor-derived peptides (pHLA). However, we and others have shown that most TCRs bind sub-optimally antigens. Uncovering molecular mechanisms define poor recognition could aid development of new targeted therapies circumnavigate these shortcomings....
CD4+ T cells are central to adaptive immunity. Their role in cross-protection viral infections such as influenza and severe acute respiratory syndrome (SARS) is well documented; however, molecular rules governing cell receptor (TCR) engagement of peptide-human leukocyte antigen (pHLA) class II less understood. Here, we exploit an aspect HLA presentation, the peptide-flanking residues (PFRs), "tune" responses within vivo model system influenza. Using a recombinant virus containing targeted...
The central immunological role of HLA class I (HLA-I) in presenting peptide Ags to cellular components the immune system has been focus intense study for >60 y. A confounding factor HLA-I extreme polymorphism these molecules. mAb W6/32 a fundamental reagent bypassing issue by recognizing an epitope that is conserved across diverse allotypes. However, despite widespread use W6/32, this Ab not definitively mapped. In study, we present crystal structure Fab fragment complex with...
CD4+ T cells are central to adaptive immunity. Their role in cross protection viral infections such as influenza and SARS is well documented, however molecular rules governing TCR engagement of peptide-HLA class-II less understood. Here we exploit a unique aspect presentation, the peptide flanking residues (PFRs), “tune” cell responses within an vivo model system influenza. Using recombinant virus containing targeted substitutions at immunodominant HLA-DR1 epitopes, demonstrate limited...
Background Major histocompatibility complex class-1-related protein (MR1), unlike human leucocyte antigen (HLA) class-1, was until recently considered to be essentially monomorphic. MR1 presents metabolites in the context of host responses bacterial infection. MR1-restricted TCRs with specificity for tumor cells have been described, raising interest their potential therapeutic application cancer treatment.1 2 The diversity MR1-ligand biology has broadened observation that single nucleotide...