A5071080814- T-cell and B-cell Immunology
- Immune Cell Function and Interaction
- Immunotherapy and Immune Responses
- Adrenal Hormones and Disorders
- Circadian rhythm and melatonin
- Chemokine receptors and signaling
- Lymphatic System and Diseases
- Childhood Cancer Survivors' Quality of Life
- IL-33, ST2, and ILC Pathways
- Hematopoietic Stem Cell Transplantation
- Growth Hormone and Insulin-like Growth Factors
- Animal testing and alternatives
- Neonatal Respiratory Health Research
- Neuropeptides and Animal Physiology
- Pancreatic function and diabetes
- Sphingolipid Metabolism and Signaling
- Cancer Cells and Metastasis
- Neuroblastoma Research and Treatments
- 3D Printing in Biomedical Research
- Eosinophilic Esophagitis
- Diabetes and associated disorders
- Retinoids in leukemia and cellular processes
- Neutropenia and Cancer Infections
- Transgenic Plants and Applications
- Signaling Pathways in Disease
University of Birmingham
2014-2023
Immune Regulation (United Kingdom)
2006-2016
Medical Research Council
2002-2016
Institute of Immunology
2015
Aire-expressing medullary thymic epithelial cells (mTECs) play a key role in preventing autoimmunity by expressing tissue-restricted antigens to help purge the emerging T cell receptor repertoire of self-reactive specificities. Here we demonstrate novel for CD4(+)3(-) inducer population, previously linked development organized secondary lymphoid structures and maintenance memory functional regulation Aire-mediated promiscuous gene expression thymus. are closely associated with mTECs adult...
Exceptionally germinal center formation can be induced without T cell help by polysaccharide-based antigens, but these centers involute massive B apoptosis at the time centrocyte selection starts. This study investigates whether cells in cell–independent antigen (4-hydroxy-3-nitrophenyl)acetyl (NP) conjugated to Ficoll undergo hypermutation their immunoglobulin V region genes. Positive controls are provided comparing same stage of development carrier-primed mice immunized with a...
A key role of the thymic medulla is to negatively select autoreactive CD4+ and CD8+ thymocytes, a process important for T cell tolerance induction. However, involvement in other aspects αβ development, including generation Foxp3+ natural regulatory cells (nTreg cells) continued maturation positively selected conventional cells, unclear. We show that newly generated CD69+Qa2− CD4 single-positive thymocytes mature late CD69−Qa2+ stage absence RelB-dependent medullary epithelial (mTECs)....
SummaryThe thymic medulla provides a specialized microenvironment for the negative selection of T cells, with presence autoimmune regulator (Aire)-expressing medullary epithelial cells (mTECs) during embryonic-neonatal period being both necessary and sufficient to establish long-lasting tolerance. Here we showed that emergence first cohorts Aire+ mTECs at this key developmental stage, prior αβ cell repertoire selection, was jointly directed by Rankl+ lymphoid tissue inducer invariant Vγ5+...
Abstract In the thymus, interactions between immature thymocytes and thymic epithelial cells (TECs) regulate development selection of self-tolerant MHC-restricted T cells. Despite importance cortical (cTEC) medullary (mTEC) in fostering cell production, events TEC are still unclear. Although precursor-product relationships during mTEC have been reported, some genetic regulators identified, stages cTEC occurring downstream recently identified bipotent cTEC/mTEC progenitors remain poorly...
The thymic medulla represents a key site for the induction of T cell tolerance. In particular, autoimmune regulator (Aire)-expressing medullary epithelial cells (mTECs) provide spectrum tissue-restricted Ags that, through both direct presentation and cross-presentation by dendritic cells, purge developing repertoire specificities. Despite this role, mechanisms Aire(+) mTEC development remain unclear, particularly those stages that occur post-Aire expression represent terminal...
In the adult thymus, development of self‐tolerant thymocytes requires interactions with thymic epithelial cells (TECs). Although both cortical and medullary TECs (cTECs/mTECs) are known to arise from common bipotent TEC progenitors, phenotype these progenitors timing emergence distinct lineages remain unclear. Here, we have investigated developmental properties during cTEC/mTEC lineage development. We show that can undergo a stepwise acquisition first cTEC then mTEC hallmarks, resulting in...
In the thymus, interactions with both cortical and medullary microenvironments regulate development of self-tolerant conventional CD4(+) CD8(+) αβT cells expressing a wide range αβTCR specificities. Additionally, cortex is also required for invariant NKT (iNKT) cells, specialized subset T that expresses restricted repertoire linked to regulation innate adaptive immune responses. Although role in this process enable recognition CD1d molecules expressed by CD4(+)CD8(+) thymocyte precursors,...
Formation of a mature thymic epithelial microenvironment is an essential prerequisite for the generation functionally competent T cell pool. It likely that recently identified precursors undergo phases proliferation and differentiation to generate cortical medullary microenvironments. The mechanisms regulating development immature cells are unknown. Here we provide evidence expansion embryonic epithelium regulated by continued presence mesenchyme. In particular, mesenchymal shown mediate...
T cell tolerance in the thymus is a key step shaping developing repertoire. Thymic medullary epithelial cells play multiple roles this process, including negative selection of autoreactive thymocytes, influencing thymic dendritic positioning, and generation Foxp3(+) regulatory cells. Previous studies show that (mTEC) development involves hemopoietic cross-talk, numerous TNFR superfamily members have been implicated process. Whereas CD40 RANK represent examples, interplay between these...
During αβT cell development, the thymus medulla represents an essential microenvironment for T tolerance. This functional specialization is attributed to its typical organized topology consisting of a branching structure that contains medullary thymic epithelial (mTEC) networks support negative selection and Foxp3+ T-regulatory (T-reg) development. Here, by performing TEC-specific deletion regulator lymphotoxin β receptor (LTβR), we show tolerance mechanisms operate independently...
Abstract αβT cell development depends upon serial migration of thymocyte precursors through cortical and medullary microenvironments, enabling specialized stromal cells to provide important signals at specific stages their development. Although conventional are subject clonal deletion in the medulla, entry into thymus medulla also fosters differentiation. For example, during postnatal periods, is involved intrathymic generation multiple lineages, notably induction Foxp3+ regulatory T...
The thymus supports multiple αβ T cell lineages that are functionally distinct, but mechanisms control this multifaceted development poorly understood. Here we examine medullary thymic epithelial (mTEC) heterogeneity and its influence on CD1d-restricted iNKT cells. We find three distinct mTEClow subsets distinguished by surface, intracellular secreted molecules, identify LTβR as a cell-autonomous controller of their development. Importantly, mTEC enables the to differentially sublineages...
Therapeutic interventions used for cancer treatment provoke thymus damage and limit the recovery of protective immunity. Here, we show that eosinophils are an essential part intrathymic type 2 immune network enables after ablative therapy. Within hours damage, undergoes CCR3-dependent colonization by peripheral eosinophils, which reestablishes epithelial microenvironments control thymopoiesis. Eosinophil regulation regeneration occurs via concerted action NKT cells trigger CCL11 production...
The thymus medulla is a key site for immunoregulation and tolerance, its functional specialisation achieved through the complexity of medullary thymic epithelial cells (mTEC). While importance function clear, production maintenance mTEC diversity remains poorly understood. Here, using ontogenetic inducible fate-mapping approaches, we identify mTEC-restricted progenitors as cytokeratin19
Abstract The thymus provides a specialized site for the production of T cells capable recognizing foreign antigens in context self–major histocompatibility complex (MHC) molecules. During development, arises from an epithelial rudiment containing bipotent progenitors that differentiate into distinct cortical and medullary to regulate maturation selection self-tolerant CD4+ CD8+ cells. In addition their differentiation, thymic undergo cellular expansion ensure sufficient intrathymic niches...
Cortical and medullary epithelium represent specialised cell types that play key roles in thymocyte development, including positive negative selection of the T repertoire. While recent evidence shows these epithelial lineages share a common embryonic origin, phenotype possible persistence such progenitor cells thymus at later stages development remain controversial. Through use panel reagents putative marker Mts24, we set out to redefine thymic epithelium. In early day (E)12 anlagen find...
Abstract The vitamin A metabolite and transcriptional modulator retinoic acid (RA) is recognized as an important regulator of epithelial cell homeostasis in several tissues. Despite the known importance compartment thymus T development selection, potential role RA regulation thymic cortical medullary has yet to be addressed. In this study, using fetal organ cultures, we demonstrate that endogenous signaling promotes (TEC) cell-cycle exit restricts TEC cellularity preferentially compartment....
Thymic epithelial cells (TECs) provide essential signals for αβT-cell development, and medullary TECs (mTECs) control T-cell tolerance through both negative selection Foxp3(+) regulatory T (Treg) cell development. Although heterogeneity within the mTEC compartment is well studied, molecular regulators of specific stages development are still poorly understood. Given importance RANK-RANKL axis in thymus medulla formation, we have used RANK Venus reporter mice to analyze ontogeny RANK(+)...
In the thymus, medullary thymic epithelial cells (mTEC) regulate T cell tolerance via negative selection and Foxp3(+) regulatory (Treg) development, alterations in mTEC compartment can lead to breakdown autoimmunity. Both receptor activator for NF-κB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) axis expression of transcriptional regulator Aire are involved regulation thymus microenvironments. However, their impact on mechanisms controlling homeostasis is poorly understood, as processes...
Members of the innate lymphoid cell (ILC) family have been implicated in development thymic microenvironments and recovery this architecture after damage. However, a detailed characterization thymus is lacking. To better understand ILC compartment, we utilized multiple vivo models including fate mapping inhibitor DNA binding-2 (Id2) expression use Id2 reporter mice. Our data demonstrate that ILCs are more prominent immediately birth, but were rapidly diluted as T-cell program increased. As...