Relevant Degree Programs
T cells form an integral part of our immune system and are essential to fight off most infections. To perform these roles, T cells must be able to discriminate between various antigens and elicit the appropriate type and the appropriate strength of response. Excessive T cell responses towards harmless antigens may result in dangerous allergies while attack against healthy cells or tissue can cause T cell-mediated self-destruction resulting in autoimmunity. By contrast, the inappropriate type or a dampened T cell response against infected or malignant cells may lead to chronic, life-threatening infections or the development of malignancies. During my career, I have acquired expertise in a wide-range of technologies including signal transduction, cellular immunology, genetic engineering of mice and mouse modeling of human diseases including infection, autoimmunity and cancer. Consequently, I am committed to understanding how T cell function can be regulated so that I can uncover new therapies for human diseases related to allergies, autoimmunity, cancer and infection.
Complete these steps before you reach out to a faculty member!
- Familiarize yourself with program requirements. You want to learn as much as possible from the information available to you before you reach out to a faculty member. Be sure to visit the graduate degree program listing and program-specific websites.
- Check whether the program requires you to seek commitment from a supervisor prior to submitting an application. For some programs this is an essential step while others match successful applicants with faculty members within the first year of study. This is either indicated in the program profile under "Requirements" or on the program website.
- Identify specific faculty members who are conducting research in your specific area of interest.
- Establish that your research interests align with the faculty member’s research interests.
- Read up on the faculty members in the program and the research being conducted in the department.
- Familiarize yourself with their work, read their recent publications and past theses/dissertations that they supervised. Be certain that their research is indeed what you are hoping to study.
- Compose an error-free and grammatically correct email addressed to your specifically targeted faculty member, and remember to use their correct titles.
- Do not send non-specific, mass emails to everyone in the department hoping for a match.
- Address the faculty members by name. Your contact should be genuine rather than generic.
- Include a brief outline of your academic background, why you are interested in working with the faculty member, and what experience you could bring to the department. The supervision enquiry form guides you with targeted questions. Ensure to craft compelling answers to these questions.
- Highlight your achievements and why you are a top student. Faculty members receive dozens of requests from prospective students and you may have less than 30 seconds to pique someone’s interest.
- Demonstrate that you are familiar with their research:
- Convey the specific ways you are a good fit for the program.
- Convey the specific ways the program/lab/faculty member is a good fit for the research you are interested in/already conducting.
- Be enthusiastic, but don’t overdo it.
G+PS regularly provides virtual sessions that focus on admission requirements and procedures and tips how to improve your application.
Graduate Student Supervision
Doctoral Student Supervision (Jan 2008 - Nov 2019)
The full abstract for this thesis is available in the body of the thesis, and will be available when the embargo expires.
Mutations in the SH2D1A gene that encodes signaling lymphocyte activation molecule (SLAM)-associated protein (SAP) cause X-linked lymphoproliferative disease (XLP), a congenital immunodeficiency defined by exquisite sensitivity to Epstein-Barr virus (EBV). Upon EBV infection, XLP patients develop fulminant infectious mononucleosis, characterized by massive expansions of EBV-infected B cells and susceptibility to malignant B cell lymphomas. The precise mechanism of how SAP mediates immunity against EBV remains unclear. Here, we utilized SAP-deficient (Sh2d1a-/-) mice to investigate the role of SAP in regulating T cell differentiation and function. We found that SAP-deficient CD4 and CD8 T cells had a diminished capacity to differentiate into IL-17-producing T helper (Th17) and T cytotoxic (Tc17) cells. The use of co-stimulating SLAM antibodies was found to augment the differentiation of IL-17-producing effectors in wild type but not Sh2d1a-/- splenic T cells under IL-17-polarizing conditions. Furthermore, Sh2d1a-/- mice were protected from experimental autoimmune encephalomyelitis (EAE) and exhibited decreased numbers of CNS-infiltrating Th17 and Tc17 effectors. Together, these results demonstrate that SAP signaling drives the differentiation and function of Th17 and Tc17 cells in vitro and in vivo. In addition, we hypothesized that SAP and SLAM family receptors may be critical for B cell-priming of antigen-specific CD8 T cells. To test this hypothesis, purified wild type and Sh2d1a-/- CD8 T cells were stimulated with various types of antigen-presenting cells (APCs) including B cells, B cell-depleted splenocytes and B lymphoma cells. We found that Sh2d1a-/- CD8 T cells exhibited diminished proliferation and effector functions when stimulated with antigen-presenting B cells or B lymphoma cells but not B cell-depleted splenocytes. In addition, wild type and Sh2d1a-/- CD8 T cells proliferated equivalently when cultured with non-SLAM family receptors-expression APCs: antigen-expressing melanoma or carcinoma cells. Together, these results identify a critical role for SAP and SLAM family receptors in the priming of CD8 T cells towards antigen-presenting B cells or B lymphoma cells. Collectively, our findings suggest that the susceptibility of XLP patients to EBV may be a consequence of virus’s B cell tropism and an inability of SAP-deficient naïve CD8 T cells to proliferate and differentiate upon encountering EBV-infected B cells.
Master's Student Supervision (2010 - 2018)
Individuals with combined immunodeficiency exhibit normal frequencies of T and B cells but suffer from severe recurrent infections. A child admitted to BCCH displayed a novel clinical presentation of combined immunodeficiency with immune dysregulation. The patient was found to inherit homozygous missense mutations in the MALT1 gene from her consanguineous parents. MALT1 is important in activating the NF-kB pathway upon TCR stimulation. MALT1 functions by two different mechanisms: (1) as a scaffolding molecule bringing CARD11 and BCL-10 to form the CBM signalosome complex and (2) as a caspase-like protease cleaving substrates to regulate NF-kB signaling. Studies in Malt1¯/¯ mice have revealed weakened T cell immunity whereas mice expressing MALT1 lacking paracaspase activity are prone to fetal autoimmunity. In addition, patients with MALT1 mutations shared similar clinical characteristics, experiencing chronic infections and gastrointestinal inflammation. Together, these findings raise questions regarding the nature of our patient’s mutant MALT1 protein and the role it plays in her pro-inflammatory phenotype. Our data have shown that MALT1 is essential for IL-2 production in CD4 T cells despite the dispensable role in regulatory T cell development. In addition, we demonstrate that MALT1 plays a crucial role in effector function of Th1 and Th17 cells. Analysis of the patient’s MALT1 scaffolding and paracaspase activity revealed that the patient’s MALT1 mutations act as a hypomorphic allele. Unlike our patient, Malt1¯/¯ mice do not exhibit constitutive immune activation and severe intestinal inflammation. A limited pathogen exposure may be responsible for the discrepancy in phenotype of the patient and Malt1¯/¯ mice. Hence, we introduced LCMV pathogen to Malt1¯/¯ mice and assessed the role of MALT1 in anti-viral T cell immune responses. Malt1¯/¯ mice exhibited severely impaired effector function of viral-specific CD4 T cells. However, we found that MALT1 is dispensable for the generation and effector function of viral-specific CD8 T cells. Further, MALT1 alters the expression of T cell differentiation markers, whereas it does not modulate activation and inhibitory receptors upon viral infection. Collectively, our studies demonstrate that MALT1 plays a pivotal role in CD4 T cell immune responses, yet is not required for CD8 T cell anti-viral immunity.
- An allosteric MALT1 inhibitor is a molecular corrector rescuing function in an immunodeficient patient (2019)
Nature Chemical Biology,
- Arp2/3 complex-driven spatial patterning of the BCR enhances immune synapse formation, BCR signaling and cell activation (2018)
- Prevention of autoimmune diabetes and islet allograft rejection by beta cell expression of XIAP: Insight into possible mechanisms of local immunomodulation. (2018)
Molecular and cellular endocrinology,
- The importance of functional validation after next-generation sequencing: evaluation of a novel CARD11 variant. (2018)
Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology,
- 2B4-SAP signaling is required for the priming of naive CD8+ T cells by antigen-expressing B cells and B lymphoma cells. (2017)
- JAK1 gain-of-function causes an autosomal dominant immune dysregulatory and hypereosinophilic syndrome. (2017)
- Pre-diagnostic genotyping identifies T1D subjects with impaired Treg IL-2 signaling and an elevated proportion of FOXP3(+)IL-17(+) cells. (2017)
- CCL22 prevents rejection of mouse islet allografts and induces donor-specific tolerance (2015)
Cell Transplantation, 24 (10), 2143-2154
- CD1d Expression and Invariant NKT Cell Responses in Herpesvirus Infections (2015)
Front. Immunol., 6
- Multiple sclerosis-associated CLEC16A controls HLA class II expression via late endosome biogenesis (2015)
Brain, 138 (6), 1531--1547
- The paracaspase MALT1 cleaves HOIL1 reducing linear ubiquitination by LUBAC to dampen lymphocyte NF-κ B signalling (2015)
Nature Communications, 6
- Combined immunodeficiency associated with homozygous MALT1 mutations (2014)
Journal of Allergy and Clinical Immunology, 133 (5), 1458--1462.e7
- Lyn Deficiency Leads to Increased Microbiota-Dependent Intestinal Inflammation and Susceptibility to Enteric Pathogens (2014)
The Journal of Immunology, 193 (10), 5249--5263
- MS-associated gene CLEC16A uses the molecular machinery of late endosomal biogenesis to control HLA-II expression in APC (2014)
Journal of Neuroimmunology, 275 (1-2), 73
- Natural killer T cell strategies to combat Epstein–Barr virus infection (2014)
OncoImmunology, 3 (4), e28329
- SLAM-SAP Signaling Promotes Differentiation of IL-17-Producing T Cells and Progression of Experimental Autoimmune Encephalomyelitis (2014)
The Journal of Immunology, 193 (12), 5841--5853
- Innate immune control of EBV-infected B cells by invariant natural killer T cells (2013)
Blood, 122 (15), 2600--2608
- Lyn-Dependent Signaling Regulates the Innate Immune Response by Controlling Dendritic Cell Activation of NK Cells (2012)
The Journal of Immunology, 188 (10), 5094--5105
- PSGL-1 Regulates the Migration and Proliferation of CD8+ T Cells under Homeostatic Conditions (2012)
The Journal of Immunology, 188 (4), 1638--1646
- Natural Killer Cells From Children With Type 1 Diabetes Have Defects in NKG2D-Dependent Function and Signaling (2011)
Diabetes, 60 (3), 857--866
- NKT Cells Are Required for Complete Freund's Adjuvant-Mediated Protection from Autoimmune Diabetes (2011)
The Journal of Immunology, 187 (6), 2898--2904
- The CaV1.4 Calcium Channel Is a Critical Regulator of T Cell Receptor Signaling and Naive T Cell Homeostasis (2011)
Immunity, 35 (3), 349--360
- Cutting Edge: Increased IL-17-Secreting T Cells in Children with New-Onset Type 1 Diabetes (2010)
The Journal of Immunology, 185 (7), 3814--3818
- Increased Fraction of IL-17 Secreting Cells in Type 1 Diabetes (2010)
Clinical Immunology, 135, S132
- NKT Cells Kill EBV Transformed B Cells following CD1d Upregulation by RARα (2010)
Clinical Immunology, 135, S137
- F.128. Natural Killer Cells from Patients with Type 1 Diabetes Exhibit Defective NKG2D Effector Function and Dysregulated NKG2D Ligand Expression (2009)
Clinical Immunology, 131, S128
- RasGRP1 Regulates Antigen-Induced Developmental Programming by Naive CD8 T Cells (2009)
The Journal of Immunology, 184 (2), 666--676
- T.2. NKT Cells and NK Cells are Required for CFA-Mediated Protection of Diabetes (2009)
Clinical Immunology, 131, S45
- Critical role for IFN-γ in natural killer cell-mediated protection from diabetes (2008)
Eur. J. Immunol., 38 (1), 82--89
- Preferential Development of CD4 and CD8 T Regulatory Cells in RasGRP1-Deficient Mice (2008)
The Journal of Immunology, 180 (9), 5973--5982
- Su.35. Epstein-Barr Virus Downregulates B Cell Surface CD1d to Evade Natural Killer T Cell Detection (2008)
Clinical Immunology, 127, S135--S136
- 115 Impaired T Cell Function and CD8 Memory Maintenance in a Novel Interleukin-7 Receptor α Knock-in Mouse (2007)
Cytokine, 39 (1), 31--32
- Chronic Immunodeficiency in Mice Lacking RasGRP1 Results in CD4 T Cell Immune Activation and Exhaustion (2007)
The Journal of Immunology, 179 (4), 2143--2152
- Impaired CD8 T cell memory and CD4 T cell primary responses in IL-7R mutant mice (2007)
Journal of Experimental Medicine, 204 (3), 619--631
- RasGRP1 Transmits Prodifferentiation TCR Signaling That Is Crucial for CD4 T Cell Development (2006)
The Journal of Immunology, 177 (3), 1470--1480
- TNF Receptor Type 2 (p75) Functions as a Costimulator for Antigen-Driven T Cell Responses In Vivo (2006)
The Journal of Immunology, 176 (2), 1026--1035
- Self-reactive memory-phenotype CD8 T cells exhibit both MHC-restricted and non-MHC-restricted cytotoxicity: A role for the T-cell receptor and natural killer cell receptors (2004)
Blood, 104 (7), 2116-2123
- RasGRP1 Transduces Low-Grade TCR Signals which Are Critical for T Cell Development, Homeostasis, and Differentiation (2002)
Immunity, 17 (5), 617--627
- Sialyltransferase specificity in selectin ligand formation (2002)
Blood, 100 (10), 3618-3625
- Developmentally Regulated Glycosylation of the CD8αβ Coreceptor Stalk Modulates Ligand Binding (2001)
Cell, 107 (4), 501--512
- p59fyn (Fyn) promotes the survival of anergic CD4- CD8- αβ TCR+ cells but negatively regulates their proliferative response to antigen stimulation (2001)
Journal of Immunology, 166 (3), 1540-1546
- p59fyn (Fyn) Promotes the Survival of Anergic CD4-CD8- TCR+ Cells but Negatively Regulates Their Proliferative Response to Antigen Stimulation (2001)
The Journal of Immunology, 166 (3), 1540--1546
- TCR/Self-Antigen Interactions Drive Double-Negative T Cell Peripheral Expansion and Differentiation into Suppressor Cells (2001)
The Journal of Immunology, 167 (11), 6188--6194
- The ST3Gal-I Sialyltransferase Controls CD8+ T Lymphocyte Homeostasis by Modulating O-Glycan Biosynthesis (2000)
Immunity, 12 (3), 273--283
- Isolation, characterization and inactivation of the mouse Mgat3 gene: the bisecting N -acetylglucosamine in asparagine-linked oligosaccharides appears dispensable for viability and reproduction (1997)
Glycobiology, 7 (1), 45--56
- Localization of the Rhodobacter capsulatus bchCA Operon Oxygen-Regulated Promoter (1990)
Current Research in Photosynthesis, , 2359--2365