John Priatel

Assistant Professor

Research Classification

Auto-Immune Diseases
Cell Signaling and Infectious and Immune Diseases
Diseases of the Immune System
Cell Therapy of Infectious and Immune Diseases

Research Interests

Autoimmunity
Immunodeficiency
Tumour immunotherapy
Viral infection
host-pathogen interactions

Relevant Degree Programs

 

Research Methodology

Mouse model systems
Flow cytometry
molecular biology
Cellular immunology

Recruitment

Master's students
Doctoral students
Any time / year round

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.

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Graduate Student Supervision

Doctoral Student Supervision (Jan 2008 - Nov 2019)
Shaping of the T cell repertoire by self and foreign antigens (2018)

The full abstract for this thesis is available in the body of the thesis, and will be available when the embargo expires.

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The role of SAP in antigen priming and differentiation of T lymphocytes (2016)

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.

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Master's Student Supervision (2010 - 2018)
The role of MALT1 in T cell immunity (2017)

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.

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Publications

 
 

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