A5071379424- T-cell and B-cell Immunology
- Immune Cell Function and Interaction
- Immunotherapy and Immune Responses
- NF-κB Signaling Pathways
- Diabetes and associated disorders
- Immunodeficiency and Autoimmune Disorders
- Immune Response and Inflammation
- CAR-T cell therapy research
- Adrenal Hormones and Disorders
- Monoclonal and Polyclonal Antibodies Research
- interferon and immune responses
- Immune responses and vaccinations
- Learning Styles and Cognitive Differences
- Hematopoietic Stem Cell Transplantation
- Reproductive System and Pregnancy
- Cell Adhesion Molecules Research
- RNA regulation and disease
- Cytomegalovirus and herpesvirus research
- Herpesvirus Infections and Treatments
- Photoreceptor and optogenetics research
- bioluminescence and chemiluminescence research
- PI3K/AKT/mTOR signaling in cancer
- Childhood Cancer Survivors' Quality of Life
- Myasthenia Gravis and Thymoma
- Adenosine and Purinergic Signaling
Queensland University of Technology
2021-2025
Monash University
2015-2023
University of Technology Sydney
2023
Australian National University
2010-2022
Australian Regenerative Medicine Institute
2017-2022
Hartford Public Library
2015
Hartford Financial Services (United States)
2015
University of Oxford
2006-2009
Acquisition of self-tolerance in the thymus requires T cells to discriminate strong versus weak cell receptor binding by self-peptide–MHC complexes. We find this discrimination is reported expression transcription factor Helios, which induced during negative selection but decreases positive selection. Helios and proapoptotic protein Bim were coinduced 55% nascent CCR7− CD4+ CD69+ thymocytes. These short-lived that up-regulated PD-1 down-regulated CD4 CD8 Bim-dependent apoptosis. also at...
MR1-restricted mucosal-associated invariant T (MAIT) cells play a unique role in the immune system. These develop intrathymically through three-stage process, but events that regulate this are largely unknown. Here, using bulk and single-cell RNA sequencing-based transcriptomic analysis mice humans, we studied changing transcriptional landscape accompanies transition each stage. Many transcripts were sharply modulated during MAIT cell development, including SLAM (signaling lymphocytic...
B cells inhabit the normal human thymus, suggesting a role in T cell selection. In this study, we report that can modulate thymic production of CD4+ Foxp3+ (regulatory [Tregs]). Mice with transgenic expression BAFF (BAFF-Tg) harbor increased numbers Helios+ Tregs and, similar to some autoimmune conditions, also exhibit colonizing thymus. Distinct intrathymic subpopulations were identified, namely B220+, IgM+, CD23(hi), CD21(int) cells; CD23(lo), CD21(lo) and population CD21(hi) cells....
Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated disease involving effector Th subsets such as Th1 and Th17. In this study, we demonstrate that mice lacking the NF-κB transcription factor family member c-Rel (rel(-/-)), which are known to be resistant EAE, show impaired Th17 development. Mixed bone marrow chimeras EAE adoptive transfer experiments deficiency of cells in rel(-/-) cell intrinsic. Consistent with finding, was activated response TCR signaling early stages...
IL-21 is a member of the common gamma-chain-dependent cytokine family and key modulator lymphocyte development, proliferation, differentiation. highly expressed in activated CD4(+) T cells plays critical role expansion differentiation Th cell subsets, Th17 follicular helper (T(FH)) cells. Because its potent activity both myeloid lymphoid immune responses, it has been implicated number autoimmune diseases also used as therapeutic agent treatment some cancers. In this study, we demonstrate...
OBJECTIVE To define cellular mechanisms by which B cells promote type 1 diabetes. RESEARCH DESIGN AND METHODS The study measured islet-specific CD4 T cell regulation in T-cell receptor transgenic mice with elevated frequencies of recognizing hen egg lysozyme (HEL) autoantigen expressed islet β-cells and thymic epithelium under control the insulin-gene promoter. effects a mutation Roquin that dysregulates follicular helper (Tfh) to B-cell activation anti-islet autoantibodies were studied, as...
Missense variants are a major source of human genetic variation. Here we analyze new mouse missense variant, Rasgrp1Anaef, with an ENU-mutated EF hand in the Rasgrp1 Ras guanine nucleotide exchange factor. Rasgrp1Anaef mice exhibit anti-nuclear autoantibodies and gradually accumulate CD44hi Helios+ PD-1+ CD4+ T cell population that is dependent on B cells. Despite reduced Rasgrp1-Ras-ERK activation vitro, thymocyte selection mostly normal vivo, although CD44 overexpressed naïve thymocytes...
Abstract In the aftermath of thymic negative selection, natural and adaptive regulatory T cells (Tregs) must acknowledge peripheral, “danger-free” self-Ag to ensure their sustained activity. this paper, we show that Tregs or transduced with cDNA for Foxp3, just like Th1 cells, express members MS4A family transmembrane molecules. Naive MS4A4B become able respond lower levels Ag. Using two members, MS4A6B, as baits in a yeast split-ubiquitin Treg library screen, demonstrate interaction each...
TGF-beta is a key immunoregulatory cytokine which supports self-tolerance by signaling to T cells. In this report, we show crucial role for cells in enabling the long-term acceptance of allografts, whether natural or induced therapeutically coreceptor and costimulation blockade. The requirement appears most pronounced during initial exposure alloantigens. We demonstrate ability direct development vitro regulatory that suppress graft rejection vivo. Such suppression was not affected...
Autoimmune polyendocrinopathy syndrome type 1 (APS1) results from homozygous Aire mutations that cripple thymic deletion of organ-specific T cells. The clinical course in man and mouse is characterized by high variability both the latent period before onset autoimmune disease specific organs affected, but reasons for this are unknown. Here we test hypothesis reflects failsafe action discrete postthymic mechanisms imposing self-tolerance peripheral -deficient mice were crossed with a uniform...
Abstract The thymus plays a crucial role in immune tolerance by exposing developing T cells (thymocytes) to myriad of self‐antigens. Strong T‐cell receptor ( TCR ) engagement induces self‐reactive thymocytes stimulating apoptosis or selection into specialized lineages, including intestinal αβ + CD 8αα intraepithelial lymphocytes IEL ). ‐intrinsic amino acid motifs that can be used predict whether will strongly remain elusive. Here, novel sequence alignment approach revealed lineages C57 BL...
Partial RAG deficiency (pRD) can manifest with systemic and tissue-specific immune dysregulation, inflammatory bowel disease (IBD) in 15% of the patients. We aimed at identifying immunopathological microbial signatures associated IBD patients pRD a mouse model (Rag1w/w) spontaneous development colitis. Rag1w/w mice showed colonic Th1/Th17 signature. Restriction fecal diversity, abundance pathogenic bacteria, depletion species producing short-chain fatty acid were observed, which impaired...
Significance Advances in organ transplantation and treatment of allergy autoimmune disease hinge upon harnessing a physiological switch that allows T cells to decide between proliferating extensively or actively becoming tolerant. The experiments presented here illuminate critical element this natural switch, Ndfip1 (neural precursor cell expressed, developmentally down-regulated protein 4 family-interacting 1), partner ubiquitin ligases induced during the first several divisions after...
Gene variants that disrupt TCR signaling can cause severe immune deficiency, yet less disruptive are sometimes associated with pathology. Null mutations of the gene encoding scaffold protein Src homology 2 domain-containing leukocyte 76 kDa (SLP-76), for example, an arrest T cell positive selection, whereas a synthetic membrane-targeted allele allows limited selection but is proinflammatory cytokine production and autoantibodies. Whether these other enigmatic outcomes due to biochemical...
NF-κB2/p100 (p100) is an inhibitor of κB (IκB) protein that partially degraded to produce the NF-κB2/p52 (p52) transcription factor. Heterozygous NFKB2 mutations cause a human syndrome immunodeficiency and autoimmunity, but whether autoimmunity arises from insufficiency p52 or IκB function mutated p100 unclear. Here, we studied mice bearing in degron, domain harbors most clinically recognized required for signal-dependent degradation. Distinct caused graded increases p100-degradation...
BackgroundBiallelic mutations in LIG4 encoding DNA-ligase 4 cause a rare immunodeficiency syndrome manifesting as infant-onset life-threatening and/or opportunistic infections, skeletal malformations, radiosensitivity and neoplasia. is pivotal during DNA repair V(D)J recombination it performs the final DNA-break sealing step.ObjectivesThis study explored whether monoallelic missense may underlie autoimmunity with autosomal dominant inheritance.MethodsExtensive flow-cytometric...
Abstract Interactions between a T cell receptor (TCR) and peptide-major histocompatibility complex (pMHC) ligand are typically mediated by noncovalent bonds. By studying cells expressing natural or engineered TCRs, here we describe covalent TCR-pMHC interactions that involve cysteine-cysteine disulfide bond the TCR peptide. introducing cysteines into known combination, demonstrate formation does not require structural rearrangement of We further show these bonds still form even when initial...
Ocular antigens are sequestered behind the blood-retina barrier and ocular environment protects tissues from autoimmune attack. The signals required to activate autoreactive T cells allow them cause disease in eye remain part unclear. In particular, consequences of peripheral presentation not fully understood. We examined expression neo-self-antigen transgenic mice expressing hen egg lysozyme (HEL) under a retina-specific promoter. High levels HEL were expressed compared low throughout...