A5027108566- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- Immunotherapy and Immune Responses
- Nuclear Receptors and Signaling
- Virus-based gene therapy research
- Macrophage Migration Inhibitory Factor
- CAR-T cell therapy research
- Glycosylation and Glycoproteins Research
- Adrenal Hormones and Disorders
- Cytokine Signaling Pathways and Interactions
- Cancer Immunotherapy and Biomarkers
- Protein Tyrosine Phosphatases
- Galectins and Cancer Biology
- Herpesvirus Infections and Treatments
- Bacteriophages and microbial interactions
- Poxvirus research and outbreaks
- Myasthenia Gravis and Thymoma
- Pain Mechanisms and Treatments
- Ion Channels and Receptors
- Exercise and Physiological Responses
- Chemokine receptors and signaling
- Fibromyalgia and Chronic Fatigue Syndrome Research
- Connexins and lens biology
- Aortic aneurysm repair treatments
- Vitamin D Research Studies
University of Alberta
2015-2025
Institut Langevin
2010
Arkema (France)
2010
University of Minnesota Medical Center
2008
University of Minnesota
2004-2007
Twin Cities Orthopedics
2007
The thymic medulla is generally held to be a specialized environment for negative selection. However, many self-reactive thymocytes first encounter ubiquitous self-antigens in the cortex. Cortical epithelial cells are vital positive selection, but whether such can also promote selection controversial. We used HYcd4 model, where T cell receptor antigen (TCR) expression appropriately timed and self-antigen drives clonal deletion male mice. demonstrated unambiguously that this event occurs...
Sequential rearrangement of the T cell receptor for antigen (TCR) β and α chains is a hallmark thymocyte development. This temporal control lost in TCR transgenics because chain expressed prematurely at CD4−CD8− double negative (DN) stage. To test importance this, we HYα physiological CD4+CD8+ positive (DP) The reduced DP increased DN cellularity typically seen was not observed when appropriate Surprisingly, antigen-driven selection events were also altered. In male mice, deletion now...
Abstract Engagement of the TCR on CD4+CD8+ thymocytes initiates either a program survival and differentiation (positive selection) or death (clonal deletion), which is dictated in large part by affinity for self-peptide-MHC complexes. Although much known about factors involved positive selection, little understood molecular mechanism leading to clonal deletion. To gain further insight into this process, we used highly physiological transgenic mouse model compare gene expression changes under...
Calnexin is a molecular chaperone and component of the quality control secretory pathway. We have generated calnexin gene-deficient mice (cnx(-/-)) showed that deficiency leads to myelinopathy. Calnexin-deficient were viable with no discernible effects on other systems, including immune function, instead they demonstrated dysmyelination as documented by reduced conductive velocity nerve fibers electron microscopy analysis sciatic spinal cord. Myelin peripheral central nervous systems...
Abstract Immunotherapy is a promising treatment strategy for many forms of cancer; however, patient response rates vary with only subset patients responding favorably within cohort. Recently, progress has been made in the development oncolytic viral therapy (OV), which uses viruses to selectively target and kill cancer cells while inducing anti-tumor immunity. Producing strong anti-cancer immune challenging, strategies direct responses toward tumor are key developing novel therapeutics....
Lymphopenia driven T cell activation is associated with autoimmunity. That lymphopenia does not always lead to autoimmunity suggests that control mechanisms may exist. We assessed the importance of co-inhibitory receptor programmed death-1 (PD-1) in lymphopenia-driven newly generated cells vs. established peripheral and thymic selection. PD-1 was required for negative selection thymus or maintenance self tolerance following transfer PD-1⁻/⁻ a lymphopenic host. In contrast, essential systemic...
25-Hydroxyvitamin D (25OHD) is a partial agonist of TRPV1 whereby 25OHD can weakly activate yet antagonize the stimulatory effects full agonists capsaicin and oleoyl dopamine. binds to within same vanilloid binding pocket as capsaicin. inhibits potentiating PKC-mediated activity. reduces T-cell activation trigeminal neuron calcium signalling mediated by These results provide evidence that novel receptor for biological actions vitamin in addition well-documented upon nuclear receptor. The may...
Positive and negative selection of thymocytes in the thymus are critical for development a mature self-tolerant T-cell repertoire. The proapoptotic Bcl-2 family member Bim is important by inducing apoptosis receiving strong signal through their antigen receptor. However, case ubiquitous self-antigens (UbA), not required clonal deletion self-reactive thymocytes, suggesting existence nonapoptotic mechanisms. Unlike UbA, to tissue-restricted antigens (TRAs) requires positive CCR7-mediated...
Abstract Neonatal and adult T cells differ in their effector functions. Although it is known that cell-intrinsic differences mature contribute to this phenomenon, the factors involved remain unclear. Given emerging evidence binding strength of a TCR for self-peptide presented by MHC (self-pMHC) impacts cell function, we sought determine whether altered thymic selection influences self-reactivity repertoire during ontogeny. We found conventional regulatory subsets thymus neonates young mice...
Germinal centers (GCs) are essential for antibody affinity maturation. GC B cells have a unique repertoire of cell surface glycans compared with naive cells, yet functional roles changes in glycosylation the to be ascribed. Detection GCs by GL7 reflects downregulation ligands CD22, an inhibitory co-receptor receptor. To test role CD22 GC, we generate mouse model that maintains on cells. With this model, demonstrate glycan remodeling plays critical maintenance GC. Sustained expression induces...
CD45 is a receptor protein-tyrosine phosphatase essential for T cell development and lymphocyte activation. It highly glycosylated, with multiple isoforms glycoforms expressed on the surface depending type stage of differentiation. Interestingly, we found two pools newly synthesized plasma membrane, one which arrived by 5 min after synthesis. The remaining pool was fully glycosylated began to arrive at ∼15 min. rapidly population possessed exclusively endoglycosidase H-sensitiveN-linked...
Strong T cell receptor (TCR) signaling largely induces death during thymocyte development, whereas weak TCR signals induce positive selection. However, some lineages require strong for differentiation through a process termed agonist The relationships that underlie these three fates are unknown. RasGRP1 is Ras activator required to transmit leading Here, we report that, despite being dispensable clonal deletion, critical selection of TCRαβ+CD8αα intraepithelial lymphocyte (IEL) progenitors...
Negative selection, primarily mediated through clonal deletion of self-reactive thymocytes, is critical for establishing self-tolerance and preventing autoimmunity. Recent studies suggest that the molecular mechanisms negative selection differ depending on thymic compartment developmental stage at which thymocytes are deleted. Using physiological HY(cd4) TCR transgenic model against ubiquitous self-antigen, we previously found one principal mediators implicated in deletion, Bim, required...
T cell education in the thymus is critical for establishing a functional, yet self-tolerant, repertoire. Negative selection key process enforcing self-tolerance. There are many questions that surround mechanism of negative selection, but it currently held apoptosis initiated by Bim and/or Nur77 selection. Recent studies, however, have questioned necessity maintaining both central and peripheral tolerance. To reconcile these apparently contradictory findings, we examined role...
T cell development is dependent on the migration of progenitor cells from bone marrow to thymus. Upon reaching thymus, progenitors undergo a complex developmental program that requires inputs various highly conserved signaling pathways including Notch and Wnt pathways. To date, Ras has not been implicated in very earliest stages differentiation, but members family activators called RasGRPs have shown be involved at multiple development. We examined early mice lacking RasGRP1, RasGRP3, 1 3....
A healthy immune system requires that T cells respond to foreign antigens while remaining tolerant self-antigens. Random rearrangement of the cell receptor (TCR) α and β loci generates a repertoire with vast diversity in antigen specificity, both self foreign. Selection during development thymus is critical for generating safe useful cells. Defects thymic selection contribute autoimmune immunodeficiency disorders(1-4). progenitors enter as double negative (DN) thymocytes do not express CD4...
Abstract Negative selection against highly self-reactive thymocytes is critical for preventing autoimmunity. Thymocyte deletion, anergy induction, and agonist are all forms of negative that can occur following a high-affinity TCR signal. Of Bim Nur77, two TCR-induced proteins with proapoptotic function, has been shown to be important clonal deletion in several model systems, whereas Nur77 was often dispensable. However, reported influence other aspects T cell development by mechanisms may...