A5014197793- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- CAR-T cell therapy research
- Immunotherapy and Immune Responses
- Cell Adhesion Molecules Research
- Immunodeficiency and Autoimmune Disorders
- IL-33, ST2, and ILC Pathways
- Myasthenia Gravis and Thymoma
- Cytokine Signaling Pathways and Interactions
- interferon and immune responses
- Immune Response and Inflammation
- Diabetes Treatment and Management
- Animal Diversity and Health Studies
- Eosinophilic Esophagitis
- Effects of Environmental Stressors on Livestock
- Hepatitis C virus research
- Algorithms and Data Compression
- Asthma and respiratory diseases
- Blood disorders and treatments
- Pancreatic function and diabetes
- Ion Channels and Receptors
- Diabetes Management and Research
- Exercise and Physiological Responses
- Ion channel regulation and function
- FOXO transcription factor regulation
National Institutes of Health
2022-2025
National Institute of Allergy and Infectious Diseases
2021-2024
University of Alberta
2013-2020
CD137 (4-1BB)-activating receptor represents a promising cancer immunotherapeutic target. Yet, the cellular program driven by and its role in immune surveillance remain unresolved. Using T cell-specific deletion agonist antibodies, we found that modulates tumor infiltration of CD8+-exhausted (Tex) cells expressing PD1, Lag-3, Tim-3 inhibitory receptors. cell-intrinsic, TCR-independent signaling stimulated proliferation terminal differentiation Tex precursor through mechanism involving RelA...
Our study shows that glucagon-like peptide-1 (GLP-1) is secreted within human islets and may play an unexpectedly important paracrine role in islet physiology pathophysiology. It known α cells rodent pancreatic are capable of secreting GLP-1, but little about the functional islet-derived GLP-1 plays islets.We used flow cytometry, immunohistochemistry, perifusions, calcium imaging techniques to analyse expression function isolated from cadaveric donors with or without type 2 diabetes. We also...
Type III interferons (IFN-lambdas(λ)) are important cytokines that inhibit viruses and modulate immune responses by acting through a unique IFN-λR1/IL-10RB heterodimeric receptor. Until now, the primary antiviral function of IFN-λs has been proposed to be at anatomical barrier sites. Here, we examine regulation IFN-λR1 expression measure downstream effects IFN-λ3 stimulation in human blood cells, compared with lung or liver epithelial cells. directly bound upregulated IFN-stimulated gene...
The integrin lymphocyte function–associated antigen 1 (LFA-1) helps to coordinate the migration, adhesion, and activation of T cells through interactions with intercellular adhesion molecule (ICAM-1) ICAM-2. LFA-1 is activated during engagement chemokine receptors cell receptor (TCR) inside-out signaling, a process that partially mediated by phosphoinositide 3-kinase (PI3K) its product phosphatidylinositol 3,4,5-trisphosphate (PIP 3 ). To evaluate potential roles PI3K in activation, we...
Abstract Hydrogen sulfide is a gaseous, reactive molecule specifically enriched in the gastrointestinal tract. Here, we uncover non-redundant role for control of both microbial and immune homeostasis gut. Notably, depletion via pharmaceutical dietary interventions led to profound collapse CD4 T cells ileum small intestine lamina propria significant impact on ecology. As result, mice with reduced within gut were deficient their ability mount cell dependent antibody responses oral vaccine....
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...
Inborn errors of IFN-γ immunity can underlie tuberculosis (TB). We report three patients from two kindreds without EBV viremia or disease but with severe TB and inherited complete ITK deficiency, a condition associated that renders immunological studies challenging. They have CD4+ αβ T lymphocytopenia concomitant expansion CD4−CD8− double-negative (DN) Vδ2− γδ lymphocytes, both displaying unique CD38+CD45RA+T-bet+EOMES− phenotype. Itk-deficient mice recapitulated an the DN lymphocyte...
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...
The immunologic mechanisms underlying pulmonary type 2 inflammation, including the dynamics of eosinophil recruitment to lungs, still need be elucidated.We sought investigate how IL-13-producing TH2 effector cells trigger migration in house dust mite (HDM)-driven allergic inflammation.Multiparameter and molecular profiling murine lungs with HDM-induced allergy was investigated absence IL-13 signaling by using IL-13Rα1-deficient mice separately through adoptive transfer CD4+ T from...
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....
T cell development is a highly dynamic process that driven by interactions between developing thymocytes and the thymic microenvironment. Upon entering thymus, earliest progenitors, called CD4(-)CD8(-) 'double negative' (DN) thymocytes, pass through checkpoint termed "β-selection" before maturing into CD4(+)CD8(+) positive' (DP) thymocytes. β-selection an important developmental during thymopoiesis where DN successfully express pre-T receptor (TCR) undergo extensive proliferation...
Several unique waves of γδ T cells are generated solely in the fetal/neonatal thymus, whereas additional cell subsets adults. One intriguing feature development is coordination differentiation and acquisition effector function within fetal thymus; however, it less clear whether this paradigm holds true adult animals. In study, we investigated relationship between maturation thymic export adult-derived thymocytes mice. Rag2pGFP model, immature (CD24+) expressed high levels GFP only a minority...
Abstract The γδ TCR instructively directs both lineage specification and effector programming of developing T cells. However, the manner in which different signal strengths other auxiliary signals coordinate downstream to regulate cell development remains unclear. In this study we characterized role Ras guanyl-releasing protein 1 (RasGRP1) While RasGRP1 was not necessary for bulk generation, found it required efficient generation Vγ4 + thymocytes, lineage-committed CD73 cells thymus...
Abstract While inputs regulating CD4 + T helper cell (Th) differentiation are well-defined, the integration of downstream signaling with transcriptional and epigenetic programs that define Th-lineage identity remain unresolved. PI3K is a critical regulator function; activating mutations affecting PI3Kδ result in an immunodeficiency multiple defects. Using mice expressing activated-PI3Kδ, we found aberrant expression proinflammatory Th1-signature genes under Th2-inducing conditions, both vivo...
Abstract In chronic infection and cancer, prolonged antigen exposure drives a state of T cell hyporesponsiveness, called exhaustion. A small subset TCF1 +progenitor exhausted stem-like cells (pTex) cells, is required to maintain (Tex) respond checkpoint blockade. Understanding mechanisms regulating these populations may help identify approaches counter Phosphatidylinositol 3-kinase-d (PI3Kd) an important component signaling. We have found that TCF-1 repressed in CD8 +T from patients with...
Abstract Activated PI3K-delta syndrome (APDS) is a primary immunodeficiency caused by heterozygous activating mutations in PI3Kδ, resulting recurrent infections as well allergic diseases. Given that APDS patients show an inability to clear respiratory pathogens (Th1) and development of diseases (Th2), we hypothesized hyperactivated PI3Kδ (Pik3cd E1020K) may alter CD4 T cell differentiation. Using vitro polarization murine naïve cells, observed increased production IFNγ from Pik3cd E1020Kmice...
Abstract Degranulation of perforin-containing cytotoxic granules is important for NK cells and CD8 T lymphocytes (CTLs) to kill infected or tumors. Defects in this pathway cause the primary form hemophagocytic lymphohistiocytosis (HLH), which known as familial HLH (FHL) syndrome. Most reported FHL causative genes encode molecules that are involved intracellular trafficking their fusion plasma membrane, followed by delivery contents into target cell through immunological synapses. However,...
Abstract IL-2 inducible T cell kinase (Itk) is a critical component of receptor (TCR) signaling required for activation PLCg and downstream transcription factors, that regulate expression effector molecules. Loss Itk impairs T-cell by modulating the strength TCR signal. −/−mice have defects in development with decreased proliferation impaired differentiation to multiple CD4 helper lineages. Most severe are seen Th9 cells, which produce cytokine, IL-9. Under conditions, −/−cells initially...
Abstract Type III interferons (IFN-lambdas(λ)) are the most recently discovered interferon cytokine family that inhibit viruses by signaling through a unique IFN-λR1/IL-10RB heterodimeric receptor. Until now, IFN-λs were thought to primarily act on anatomical barrier epithelial cells, neutrophils and subset of dendritic although majority studies have been performed in mice. Here, we examine regulation IFN-λR1 expression downstream effects IFN-λ3 stimulation primary human blood immune cells...