个人简介
Education & Training
Postdoctoral training, Cellular Biology & Viral Immunology Sections, Laboratory of Viral Diseases, National Institute of Allergy & Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA. Mentors: Drs. Jonathan Yewdell & Jack Bennink
Ph.D., Immunology, Dept. of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada. Mentor: Dr. David Hoskin
M.Sc., Tumor and Neurohormonal Immunology, Dept. of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada. Mentor: Dr. Istvan Berczi
Doctorate, Laboratory Medicine, National (Shaheed Beheshti) University of Medical Sciences, Tehran, Iran. Mentors: Drs. Nayer Rassaian, Mohammad Moslemizadeh & Ladan Gohari
Associate Degree, Medical Laboratory Technology, Jondi Shapour University, Ahwaz, Iran
Honors, Awards, & Distinctions
Election to the Canadian Society for Immunology (CSI) Council, 2013-2015
Appreciation Certificate from Sanofi-Aventis Biotalent Challenge, 2011
Canada Research Chair in Viral Immunity & Pathogenesis (Tier 2), Government of Canada, 2010-2015
Early Researcher Award, The Ontario Ministry of Research and Innovation, 2009-2014
New Research and Scholarly Initiative Award, Western University, 2007
Canadian Society for Immunology (CSI) Junior Investigator Travel Award (to attend the 13th International Congress of Immunology, Rio de Janeiro, Brazil), 2007
12th International Congress of Immunology (ICI/FOCIS, Montreal) Travel Award, 2004
Fogarty International Postdoctoral Fellowship Award, National Institutes of Health (NIH), 2003-04, 2004-05, 2005-06
Dalhousie Inflammation Group Travel Award, 2001
Dalhousie Faculty of Graduate Studies Student Travel Grant, 2001
Izaac Walton Killam Memorial Scholarship (Dalhousie University's most prestigious graduate student award), 2000-01, 2001-02, 2002-03
Manitoba Medical Services Foundation Morris/Neaman Award for Excellence in Research (in recognition of the best M.Sc. thesis in the Faculty of Medicine), 2000
Dalhousie Faculty of Graduate Studies Scholarship, 2000
Natural Sciences and Engineering Research Council of Canada (NSERC) Postgraduate Scholarship (Doctoral), 2000-02
Dalhousie Inflammation Group Studentship, 1999
Dalhousie Graduate Student Award, 1999
University of Manitoba Graduate Fellowship, 1999-2000 & 2000-01 (declined)
Manitoba Medical College Foundation Research Poster Award, 1999
研究领域
1. CD8+ T cell responses to viral and tumor antigens
CD8+ T cells (TCD8) are a very important subset of T lymphocytes that participate in immune responses of adaptive nature to intracellular microorganisms (e.g., viral pathogens) and in immune surveillance against spontaneously arising neoplastic cells. On the other hand, harmful and undesired TCD8 activation is encountered in transplant rejection and in autoimmune disorders, in which grafted tissues and self components are seen as foreign by the immune system, respectively. Understanding TCD8 activation cascades and cellular and molecular mechanisms responsible for positive and negative modulation of TCD8 responses are therefore of prime importance. In clinical settings, consistent efforts are being made to boost TCD8 responses in infectious diseases and in cancer patients, whereas tolerizing autoreactive and alloreactive TCD8 is considered an ultimate goal in autoimmunity and organ transplantation, respectively.
TCD8 activation is initiated by professional antigen (Ag) presenting cells (pAPCs), particularly dendritic cells (DCs), which process and load 8-11-amino acid residue-long antigenic peptides onto their major histocompatibility complex (MHC) class I molecules for presentation to naïve TCD8 bearing a T cell receptor (TCR) of unique specificity. This highly specific interaction delivers “signal 1” to TCD8. Signal 1 is necessary but not sufficient for optimal T cell activation, which also requires a second or costimulatory signal provided by other molecular interactions between T cells and pAPCs. In fact, TCR triggering in the absence of appropriate costimulatory signaling may lead to a state of T cell unresponsiveness called anergy or even T cell death by apoptosis.
TCD8 are activated through direct priming or cross-priming. Direct priming of TCD8 occurs when endogenous Ags such as viruses propagating within the cytosol of a pAPC provide the substrate for Ag processing. However, many viruses avoid pAPCs or interfere with their endogenous pathway of Ag processing and presentation. Such viruses are typically dealt with by the exogenous pathway leading to TCD8 activation via cross-priming. Cross-priming refers to a process in which a pAPC acquires exogenous antigenic substrates from a donor cell (e.g., a virus-infected cell), which is not capable of priming naïve TCD8 on its own. Cross-priming is a robust phenomenon in development of TCD8 responses against viral pathogens, tumor cells and transplanted cells. It is noteworthy that DCs can also capture “pre-made” peptide:MHC complexes from other cells including dead or dying cells for presentation to TCD8. In this pathway, there is no need for further processing of the acquired complexes. The term “cross-dressing” has been coined to describe this phenomenon. “Cross-dressed” APCs have since been implicated in inducing TCD8 responses to tumor cells as well as to cancer vaccines.
A puzzling feature of TCD8 responses is immunodominance, which dictates that out of thousands of peptides harbored by complex Ags, only a selected few elicit measurable TCD8 responses of varying magnitude. This establishes a hierarchy among Ag-specific TCD8 clones. Accordingly, immunodominant epitopes provoke robust TCD8 responses, whereas subdominant epitopes activate TCD8 clones that occupy modest ranks in the hierarchy. The reason for immunodominance is unknown. Several factors are known to shape TCD8 hierarchies. These include the abundance of foreign gene products and the efficiency of their degradation by proteasomes, the rate and degenerate specificity of peptide transport into the endoplasmic reticulum (ER), the binding affinity of peptides for MHC class I molecules within the ER, and the existence of epitope-specific TCD8 within the host T cell repertoire. Our previous work has revealed a novel role for the template-independent DNA polymerase terminal deoxynucleotidyl transferase (TdT) in shaping TCD8 immunodominance. We also recently discovered that a serine-threonine protein kinase called the mammalian target of rapamycin (mTOR) moderates immunodominance disparities in mouse TCD8 responses against a clinically relevant tumor Ag called simian virus 40 (SV40) large T Ag.
Our research team investigates various aspects of TCD8 responses, including but not limited to cross-priming, immunodominance and cytotoxic effector functions in the context of infection with viral pathogens such as influenza A viruses and immune responses to tumor Ags (e.g., large T Ag).
2. Means and modes of invariant natural killer T cell activation
Invariant natural killer T (iNKT) cells are rare but remarkably potent lymphocytes that link the innate and adaptive arms of immune responses. They are unique in several ways. First, they express an invariant T cell receptor (iTCR) that can unusually recognize glycolipid Ags in the context of the MHC class I-like molecule CD1d. Second, they contain messenger RNA for pro- and anti-inflammatory cytokines, typified by interferon (IFN)-γ and interleukin (IL)-4, respectively. As such, they can secrete large quantities of immunomodulatory cytokines early in the course of an immune response, thus shaping the nature of the ongoing or upcoming response.
Several scientists working in our lab are interested in various aspects of iNKT cell immunobiology, including their signaling pathways, costimulatory and coinhibitory requirements, interaction with other immunocytes and their potential therapeutic applications in various diseases. We were the first to identify the p38 MAP kinase as a negative regulator of iNKT cell responses, and glycosylphosphatidylinositol (GPI)-anchored proteins as non-classical costimulators of iNKT cells. In collaboration with Dr. John McCormick’s group at Western, we recently discovered that both mouse and human iNKT cells can be directly activated by group II bacterial superantigens (SAgs). We also reported the beneficial outcome of skewing iNKT cell responses towards a T helper (Th)-2-type phenotype in preventing cardiac allograft rejection and in citrulline-induced autoimmune arthritis.
The recognition of CD1d:glycolipid complexes by the iTCR is highly conserved throughout the mammalian evolution to the extent that mouse iTCR can recognize human CD1d and vice versa. In addition, prototype glycolipid agonists of mouse iNKT cells can also typically activate human iNKT cells. Therefore, findings obtained from mouse models are likely to be translatable to the clinic. In fact, iNKT cell glycolipid agonists have been employed and showed promise in several clinical trials for cancer and viral diseases.
3. Generation and modulation of superantigen-induced T cell responses
Superantigens (SAgs) are microbial toxins that induce massive T cell activation and cytokine secretion in a non-specific manner. Despite intense investigation on these molecules, our understanding of how SAg-triggered responses are regulated by various components of the immune system and also by the very bacteria that produce SAgs is far from clear. We reported that T cell responses to the prototype staphylococcal SAg staphylococcal enterotoxin B (SEB) can be downregulated by the innate immunomodulatory protein lactoferin. We also recently identified iNKT cells as an important effector cell type responding to bacterial SAgs. Our team continues to investigate the biology of SAgs independently and also in collaboration with members of the Superantigen Interest Group at Western.
近期论文
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Anantha RV, Mazzuca DM, Xu SX, Porcelli SA, Fraser DD, Martin CM, Welch I, Mele T, Haeryfar SM, McCormick JK: Th2-polarized invariant natural killer T cells reduce disease severity in acute intra-abdominal sepsis. Clinical & Experimental Immunology 2014 (in press) [PMID:24965554]
Anantha RV, Jegatheswaran J, Pepe DL, Priestap F, Delport J, Haeryfar SM, McCormick JK, Mele T: Risk factors for mortality among Canadian patients with Staphylococcus aureus bacteremia: a single-centre retrospective cohort study. CMAJ Open 2014 (in press)
Xu SX, Gilmore KJ, Szabo PA, Baroja Zeppa JJ, Baroja ML, Haeryfar SM, McCormick JK: Superantigens subvert the neutrophil response to promote abscess formation and enhance Staphylococcus aureus survival in vivo. Infection and Immunity 2014 (in press) [PMID:24914221]
Kasper KJ, Zeppa JJ, Wakabayashi AT, Xu SX, Mazzuca DM, Welch I, Baroja ML, Kotb M, Cairns E, Cleary PP, Haeryfar SM, McCormick JK: Bacterial superantigens promote acute nasopharyngeal infection by Streptococcus pyogenes in a human MHC class II-dependent manner. PLoS Pathogens 2014, 10(5): e1004155 [PMID:24875883]
Bellemore SM, Nikoopour E, Au BCY, Krougly O, Lee-Chan E, Haeryfar SM, Singh B: Anti-atherogenic peptide Ep1.B derived from apolipoprotein E induces immunomodulatory plasmacytoid dendritic cells. Clinical & Experimental Immunology 2014 (in press) [PMID:24784480]
Shrum B, Anantha RV, Xu SX, Donnelly M, Haeryfar SM, McCormick JK, Mele T: A robust scoring system to evaluate sepsis severity in an animal model. BMC Research Notes 2014, 7(1): 233 [PMID:24725742]
Woods MW, Tong JG, Tom SK, Szabo PA, Cavanagh PC, Dikeakos JD, Haeryfar SM, Barr SD: Interferon-induced HERC5 is evolving under positive selection and inhibits HIV-1 particle production by a novel mechanism targeting Rev/RRE-dependent RNA nuclear export. Retrovirology 2014, 11(1): 27 [PMID:24693865]
Patterson KG, Dixon Pittaro JL, Bastedo PS, Hess DA, Haeryfar SM, McCormick JK: Control of established colon cancer xenografts using a novel humanized single chain antibody-streptococcal superantigen fusion protein targeting the 5T4 oncofetal antigen. PLoS ONE 2014, 9(4): e95200 [PMID:24736661]
Villanueva AI, Haeryfar SM, Mallard BA, Kulkarni RR, Sharif S: Functions of invariant natural killer T cells are modulated by Toll-like receptor ligands and interferon-alpha. Innate Immunity 2014 (in press) [PMID:24934453]
Rytelewski M, Meilleur CE, Yekta MA, Szabo PA, Garg N, Schell TD, Jevnikar AM, Sharif S, Singh B, Haeryfar SM: Suppression of immunodominant antitumor and antiviral CD8+ T cell responses by indoleamine 2,3-dioxygenase. PLoS ONE 2014, 9(2): e90439 [PMID:24587363]
Nazemi A, Haeryfar SM, Gillies ER: Multifunctional dendritic sialopolymersomes: their lectin binding and drug release properties. Langmuir 2013, 29(21): 6420-8 [PMID: 23621407]
Kulkarni R, Villanueva AI, Elwadli I, Jayanth P, Read LR, Haeryfar SM, Sharif S: Costimulatory activation of murine invariant natural killer T cells by Toll-like receptor agonists. Cellular Immunology 2012, 277(1-2): 33-43 [PMID: 22795895]
Maleki Vareki S, Harding MJ, Waithman J, Zanker D, Shivji AN, Rytelewski M, Mazzuca DM, Yekta MA, Chen W, Schell TD, Haeryfar SM: Differential regulation of simultaneous antitumor and alloreactive CD8+ T-cell responses in same host by rapamycin. American Journal of Transplantation 2012, 12(1): 233-9 [PMID: 22026814]
Hayworth JL, Mazzuca DM, Maleki Vareki S, Welch I, McCormic JK, Haeryfar SM: CD1d-independent activation of mouse and human iNKT cells by bacterial superantigens. Immunology and Cell Biology 2012, 90(7): 699-709 [PMID: 22041925]
Walker KM, Rytelewski M, Mazzuca DM, Meilleur SA, Mannik LA, Yue D, Brintnell WC, Welch I, Carins E, Haeryfar SM: Preventing and curing citrulline-induced autoimmune arthritis in a humanized mouse model using a Th2-polarizing iNKT cell agonist. Immunology and Cell Biology 2012, 90(6): 630-9 [PMID: 21912419]
Blumenfeld HJ, Tohn R, Haeryfar SM, Liu Y, Savage PB, Delovitch TL: Structure-guided design of an invariant natural killer T cell agonist for optimum protection from type 1 diabetes in non-obese diabetic mice. Clinical and Experimental Immunology 2011, 166(1): 121-33 [PMID: 21910729]
Tohn R, Blumenfeld H, Haeryfar SM, Veerapen N, Besra GS, Porcelli SA, Delovitch TL: Stimulation of a shorter duration in the state of anergy by an invariant natural killer T cell agonist enhances its efficiency of protection from type 1 diabetes. Clinical and Experimental Immunology 2011, 164(1): 26-41 [PMID: 21361909]
Recommended by the Faculty of 1000
van den Heuvel MJ, Garg N, Van Kaer L, Haeryfar SM: NKT cell costimulation: experimental progress and therapeutic promise. Trends in Molecular Medicine 2011, 17(2): 65-77 [PMID: 21087900]
Mannik LA, Chin-Yee I, Sharif S, Van Kaer L, Delovitch TL, Haeryfar SM: Engagement of glycosylphosphatidylinositol(GPI)-anchored proteins results in enhanced mouse and human iNKT cell responses. Immunology 2011, 132(3): 361-75 [PMID: 21070234]
Stuart JK, Bisch SP, Leon-Ponte M, Hayatsu J, Mazzuca DM, Maleki Vareki S, Haeryfar SM: Negative modulation of invariant natural killer T cell responses to glycolipid antigens by p38 MAP kinase. International Immunopharmacology 2010, 10: 1068-76 [PMID: 20584631]
Yue D, Brintnell W, Mannik LA, Christie D, Haeryfar SM, Madrenas J, Chakrabarti S, Bell DA, Cairns E: CTLA4-Ig blocks the development and progression of citrullinated human fibrinogen-induced arthritis in DR4 transgenic mice. Arthritis & Rheumatism 2010, 62(10): 2941-52 [PMID: 20533540]
Kulkarni RR, Haeryfar SM, Sharif S: The invariant NKT cell subset in anti-viral defenses: A dark horse in anti-influenza immunity? Journal of Leukocyte Biology 2010, 88(4): 635-43 [PMID: 20519638]
Haghighi HR, Read LR, Mohammadi H, Pei Y, Ursprung C, Nagy E, Behboudi S, Haeryfar SM, Sharif S: Characterization of host responses against a recombinant fowlpox virus-vectored vaccine expressing the hemagglutinin antigen of an avian influenza virus. Clinical and Vaccine Immunology 2010, 17(3): 454-63 [PMID: 20071494]
Haghighi HR, Read LR, Haeryfar SM, Behboudi S, Sharif S: Identification of a dual-specific T cell epitope of the hemagglutinin antigen of an H5 avian influenza virus in chickens. PLoS ONE 2009, 4(11): e7772 [PMID: 19901990]
Haeyworth JL, Kasper KJ, Leon-Ponte M, Herfst CA, Yue D, Brintnell WC, Mazzuca DM, Heinrichs DE, Cairns E, Madrenas J, Hoskin DW, McCormick JK, Haeryfar SM: Attenuation of massive cytokine response to the staphylococcal enterotoxin B superantigen by the innate immunomodulatory protein lactoferrin. Clinical and Experimental Immunology 2009, 157(1): 60-70 [PMID: 19659771]
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