A5017696973- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- Immune cells in cancer
- Cancer Immunotherapy and Biomarkers
- Immunotherapy and Immune Responses
- CAR-T cell therapy research
- Chemokine receptors and signaling
- Immune Response and Inflammation
- Atherosclerosis and Cardiovascular Diseases
- Cytokine Signaling Pathways and Interactions
- Immune responses and vaccinations
- Gut microbiota and health
- Protein Tyrosine Phosphatases
- Single-cell and spatial transcriptomics
- Vaccine Coverage and Hesitancy
- Cancer Cells and Metastasis
- Hepatitis C virus research
- Galectins and Cancer Biology
- Reproductive System and Pregnancy
- NF-κB Signaling Pathways
- Hepatitis B Virus Studies
- Diabetes and associated disorders
- Psoriasis: Treatment and Pathogenesis
Princess Margaret Cancer Centre
2017
Ontario Institute for Cancer Research
2010-2014
University of Toronto
2009-2014
University Health Network
2008-2013
University of British Columbia
2003-2007
Bipar
2007
Infections with HIV, hepatitis B virus, and C virus can turn into chronic infections, which currently affect more than 500 million patients worldwide. It is generally thought that virus-mediated T-cell exhaustion limits function, thus promoting disease. Here we demonstrate natural killer (NK) cells have a negative impact on the development of immunity by using murine lymphocytic choriomeningitis virus. NK cell-deficient (Nfil3 −/− , E4BP4 ) mice exhibited higher virus-specific response. In...
Loss of interleukin (IL)-7 or the IL-7 receptor alpha (IL-7Rα, CD127) results in severe immunodeficiencies mice and humans. To more precisely identify signals governing function vivo, we have disrupted IL-7Rα Y449XXM motif by knock-in mutagenesis (IL-7Rα449F). Thymic precursors were reduced number IL-7Rα449F mice, but marked contrast to IL-7Rα−/− knockout thymocytes peripheral T cells developed normally. Strikingly, Listeria infection revealed that CD4 CD8 had different requirements for...
The protein-tyrosine phosphatase Shp1 is expressed ubiquitously in hematopoietic cells and generally viewed as a negative regulatory molecule. Mutations Ptpn6, which encodes Shp1, result widespread inflammation premature death, known the motheaten (me) phenotype. Previous studies identified regulator of TCR signaling, but severe systemic me mice may have confounded our understanding function T cell biology. To define cell–intrinsic role we characterized with cell–specific deletion (Shp1fl/fl...
CD8(+) T cells depend on the alphabeta TCR for Ag recognition and function. However, Ag-activated can also express receptors of innate immune system. In this study, we examined expression NK a population expressing high levels CD44 (CD8(+)CD44(high) cells) from normal mice. These are distinct conventional memory they proliferate become activated in response to IL 2 via CD48/CD2-dependent mechanism. Before activation, low or undetectable but upon activation with IL-2 expressed significant...
Abstract Interleukin‐1 receptor‐associated kinase (IRAK)‐4 is a serine‐threonine that plays an important role in innate and adaptive immune responses. While the requirement of IRAK‐4 activity has been studied context IL‐1R signaling, it not clear whether requires its function for all roles system. kinase‐dead knock‐in (IRAK‐4KD/KD) mice were generated to further elucidate required induce cytokine production. IRAK‐4KD/KD impaired their ability produce cytokines response vivo challenge with...
Abstract We have recently described a population of self-Ag-specific murine CD8+ T cells with memory phenotype that use receptors both the adaptive and innate immune systems in detection transformed infected cells. In this study we show upon activation IL-2 or without Ag, between 10 20% activated self-specific express low affinity FcR for IgG. By contrast, all IL-2-activated NK high levels FcR. The comprises FcγRIIIα FcRγ subunits. However, subunit also associates CD3 complex, association...
Acute infection is known to induce strong anti-tumor immune responses, but clinical translation has been hindered by the lack of an effective strategy safely and consistently provoke a therapeutic response. These limitations are overcome with novel treatment approach involving repeated subcutaneous delivery Klebsiella-derived investigational immunotherapeutic, QBKPN. In preclinical models lung cancer, QBKPN administration showed anti-cancer efficacy, which was dependent on Klebsiella...
TCR signaling plays a governing role in both the survival and differentiation of bipotent double-positive thymocytes into CD4(+) CD8(+) single-positive T cell lineages. A central mediator this developmental program is small GTPase Ras, emitting cytoplasmic signals through downstream MAPK pathways eventually affecting gene expression. signal transduction orchestrates activation Ras by integrating at least two Ras-guanyl nucleotide exchange factors, RasGRP1 Sos. In study, we have characterized...
Although toll-like receptor (TLR) signals are critical for promoting antigen presenting cell maturation, it remains unclear how stimulation via different TLRs influence dendritic (DC) function and the subsequent adaptive response in vivo. Furthermore, relationship between TLR-induced cytokine production by DCs consequences on induction of a functional immune is not clear. We have established murine model to examine whether TLR3 or TLR4 mediated DC maturation has an impact cytokines required...
Abstract Self-specific CD8 T cells, which are selected by high-affinity interactions with self-Ags, develop into a lineage distinct from conventional cells. We have previously shown that these self-specific cells acquire phenotypic and functional similarities to of the innate immune system including expression receptors associated NK In this study, we show ability produce large amounts IFN-γ in response infection Listeria monocytogenes bystander fashion. The rapid production is dramatic...
Abstract H2-M3-restricted CD8+ T cells provide early protection against bacterial infections. In this study, we demonstrate that activated signals for efficient CD4+ cell priming. C57BL/6 mice immunized with dendritic coated the MHC class II-restricted listeriolysin O peptide LLO190–201 (LLO) generated capable of responding to Listeria monocytogenes (LM) infection. Inclusion a formylated fMIGWII (fMIG), but not Ia-restricted peptides, during immunization LLO significantly increased...
Abstract Recent developments in understanding how the functional phenotype of innate immune system is programmed has led to paradigm-shifting views on immunomodulation. These advances have overturned two long-held dogmas: (1) only adaptive immunity confers immunological memory; and, (2) lacks specificity. This work describes observation that effector cells appear be differentially recruited specific pathological sites when mobilized by distinct inactivated bacterial-based stimuli...
While immunotherapies such as immune checkpoint blockade and adoptive T-cell therapy improve survival for a subset of human malignancies, many patients fail to respond. Phagocytes including dendritic cells (DC), monocytes, macrophages (MF) orchestrate innate adaptive responses against tumors. However, tumor-derived factors may limit immunotherapy effectiveness by altering phagocyte signal transduction, development, activity. Using Cytometry Time-of-Flight, we found that GCSF altered myeloid...
Abstract The tyrosine phosphatase Shp1 is expressed ubiquitously in hematopoietic cells and generally viewed as a negative regulator. Null mutations Ptpn6, which encodes Shp1, result the motheaten phenotype, characterized by widespread inflammation that causes death 3-4 weeks of age. Previous studies mice identified regulator TCR signaling, but severe these could have confounded our understanding function T cell biology. To define intrinsic role we cell-specific conditional knockout mice....
Although the role of T cells in autoimmunity has been explored for many years, mechanisms leading to initial priming an autoimmune cell response remain enigmatic. The ‘hit and run’ model suggests that self-antigens released upon death can provide signal a self-sustaining response. Using novel transgenic mouse where we could induce release via caspase-dependent apoptosis. We tracked fate CD8+ specific self-antigen. Our studies demonstrated antigens from apoptotic were cross-presented by...
Infections with hepatitis B virus and C can turn into chronic infections, which currently affect more than millions of patients worldwide. Virus mediated T cell exhaustion results in limited function thus promoting infection disease. Here we demonstrate that NK cells have a negative impact on the development immunity using murine lymphocytic choriomeningitis (LCMV). deficient (nfil3-/-, E4BP4-/-) mice exhibited higher specific response. Accordingly, depletion caused enhanced viral induced WT...
<p>CyTOF panels</p>
<p>Supplementary Figure S2 compares the immune cell content in peripheral blood and spleens from immunocompetent, immunocompromised G-CSFR-/- mice harboring MT or MTG-CSF-/- tumors.</p>
<p>Supplementary Figure S4 shows that G-CSF and G-CSFR signaling inhibit DC development activation, in DCs derived a OP9-DLL1 co-culture system.</p>
<p>Supplementary Figure S3 shows deep phenotyping of Neut/MDSCs and B cells in the bone marrow mice bearing MT or MTG-CSF-/- tumors, using FlowSOM applied tSNE maps.</p>