Bio

Honors & Awards


  • Canadian Institutes of Health Research Fellow, Canadian Institutes of Health Research (2014-present)

Professional Education


  • Bachelor of Science, McGill University (2003)
  • Doctor of Philosophy, University of Toronto (2011)

Stanford Advisors


Publications

Journal Articles


  • iRhom2 Regulation of TACE Controls TNF-Mediated Protection Against Listeria and Responses to LPS SCIENCE McIlwain, D. R., Lang, P. A., Maretzky, T., Hamada, K., Ohishi, K., Maney, S. K., Berger, T., Murthy, A., Duncan, G., Xu, H. C., Lang, K. S., Haeussinger, D., Wakeham, A., Itie-Youten, A., Khokha, R., Ohashi, P. S., Blobel, C. P., Mak, T. W. 2012; 335 (6065): 229-232

    Abstract

    Innate immune responses are vital for pathogen defense but can result in septic shock when excessive. A key mediator of septic shock is tumor necrosis factor-? (TNF?), which is shed from the plasma membrane after cleavage by the TNF? convertase (TACE). We report that the rhomboid family member iRhom2 interacted with TACE and regulated TNF? shedding. iRhom2 was critical for TACE maturation and trafficking to the cell surface in hematopoietic cells. Gene-targeted iRhom2-deficient mice showed reduced serum TNF? in response to lipopolysaccharide (LPS) and could survive a lethal LPS dose. Furthermore, iRhom2-deficient mice failed to control the replication of Listeria monocytogenes. Our study has identified iRhom2 as a regulator of innate immunity that may be an important target for modulating sepsis and pathogen defense.

    View details for DOI 10.1126/science.1214448

    View details for Web of Science ID 000299033100056

    View details for PubMedID 22246778

  • T-cell STAT3 is required for the maintenance of humoral immunity to LCMV. European journal of immunology McIlwain, D. R., Grusdat, M., Pozdeev, V. I., Xu, H. C., Shinde, P., Reardon, C., Hao, Z., Beyer, M., Bergthaler, A., Häussinger, D., Nolan, G. P., Lang, K. S., Lang, P. A. 2015; 45 (2): 418-427

    Abstract

    STAT3 is a critical transcription factor activated downstream of cytokine signaling and is integral for the function of multiple immune cell types. Human mutations in STAT3 cause primary immunodeficiency resulting in impaired control of a variety of infections, including reactivation of latent viruses. In this study, we investigate how T-cell functions of STAT3 contribute to responses to viral infection by inducing chronic lymphocytic choriomeningitis virus (LCMV) infection in mice lacking STAT3 specifically in T cells. Although mice with conditional disruption of STAT3 in T cells were able to mount early responses to viral infection similar to control animals, including expansion of effector T cells, we found generation of T-follicular helper (Tfh) cells to be impaired. As a result, STAT3 T cell deficient mice produced attenuated germinal center reactions, and did not accumulate bone marrow virus specific IgG-secreting cells, resulting in failure to maintain levels of virus-specific IgG or mount neutralizing responses to LCMV in the serum. These effects were associated with reduced control of viral replication and prolonged infection. Our results demonstrate the importance of STAT3 in T cells for the generation of functional long-term humoral immunity to viral infections.

    View details for DOI 10.1002/eji.201445060

    View details for PubMedID 25393615

  • IRF4 and BATF are critical for CD8(+) T-cell function following infection with LCMV CELL DEATH AND DIFFERENTIATION Grusdat, M., McIlwain, D. R., Xu, H. C., Pozdeev, V. I., Knievel, J., Crome, S. Q., Robert-Tissot, C., Dress, R. J., Pandyra, A. A., Speiser, D. E., Lang, E., Maney, S. K., Elford, A. R., Hamilton, S. R., Scheu, S., Pfeffer, K., Bode, J., Mittruecker, H., Lohoff, M., Huber, M., Haeussinger, D., Ohashi, P. S., Mak, T. W., Lang, K. S., Lang, P. A. 2014; 21 (7): 1050-1060

    Abstract

    CD8(+) T-cell functions are critical for preventing chronic viral infections by eliminating infected cells. For healthy immune responses, beneficial destruction of infected cells must be balanced against immunopathology resulting from collateral damage to tissues. These processes are regulated by factors controlling CD8(+) T-cell function, which are still incompletely understood. Here, we show that the interferon regulatory factor 4 (IRF4) and its cooperating binding partner B-cell-activating transcription factor (BATF) are necessary for sustained CD8(+) T-cell effector function. Although Irf4(-/-) CD8(+) T cells were initially capable of proliferation, IRF4 deficiency resulted in limited CD8(+) T-cell responses after infection with the lymphocytic choriomeningitis virus. Consequently, Irf4(-/-) mice established chronic infections, but were protected from fatal immunopathology. Absence of BATF also resulted in reduced CD8(+) T-cell function, limited immunopathology, and promotion of viral persistence. These data identify the transcription factors IRF4 and BATF as major regulators of antiviral cytotoxic T-cell immunity.

    View details for DOI 10.1038/cdd.2014.19

    View details for Web of Science ID 000337234200003

    View details for PubMedID 24531538

  • iRhom2 controls the substrate selectivity of stimulated ADAM17-dependent ectodomain shedding PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Maretzky, T., McIlwain, D. R., Issuree, P. D., Li, X., Malapeira, J., Amin, S., Lang, P. A., Mak, T. W., Blobel, C. P. 2013; 110 (28): 11433-11438

    Abstract

    Protein ectodomain shedding by ADAM17 (a disintegrin and metalloprotease 17), a principal regulator of EGF-receptor signaling and TNF? release, is rapidly and posttranslationally activated by a variety of signaling pathways, and yet little is known about the underlying mechanism. Here, we report that inactive rhomboid protein 2 (iRhom2), recently identified as essential for the maturation of ADAM17 in hematopoietic cells, is crucial for the rapid activation of the shedding of some, but not all substrates of ADAM17. Mature ADAM17 is present in mouse embryonic fibroblasts (mEFs) lacking iRhom2, and yet ADAM17 is unable to support stimulated shedding of several of its substrates, including heparin-binding EGF and Kit ligand 2 in this context. Stimulated shedding of other ADAM17 substrates, such as TGF?, is not affected in iRhom2(-/-) mEFs but can be strongly reduced by treating iRhom2(-/-) mEFs with siRNA against iRhom1. Activation of heparin-binding EGF or Kit ligand 2 shedding by ADAM17 in iRhom2(-/-) mEFs can be rescued by wild-type iRhom2 but not by iRhom2 lacking its N-terminal cytoplasmic domain. The requirement for the cytoplasmic domain of iRhom2 for stimulated shedding by ADAM17 may help explain why the cytoplasmic domain of ADAM17 is not required for stimulated shedding. The functional relevance of iRhom2 in regulating shedding of EGF receptor (EGFR) ligands is established by a lack of lysophasphatidic acid/ADAM17/EGFR-dependent crosstalk with ERK1/2 in iRhom2(-/-) mEFs, and a significant reduction of FGF7/ADAM17/EGFR-stimulated migration of iRhom2(-/-) keratinocytes. Taken together, these findings uncover functions for iRhom2 in the regulation of EGFR signaling and in controlling the activation and substrate selectivity of ADAM17-dependent shedding events.

    View details for DOI 10.1073/pnas.1302553110

    View details for Web of Science ID 000321827000058

    View details for PubMedID 23801765

  • Reactive oxygen species delay control of lymphocytic choriomeningitis virus. Cell death and differentiation Lang, P. A., Xu, H. C., Grusdat, M., McIlwain, D. R., Pandyra, A. A., Harris, I. S., Shaabani, N., HONKE, N., Maney, S. K., Lang, E., Pozdeev, V. I., Recher, M., Odermatt, B., Brenner, D., Häussinger, D., Ohashi, P. S., Hengartner, H., Zinkernagel, R. M., Mak, T. W., Lang, K. S. 2013; 20 (4): 649-658

    Abstract

    Cluster of differentiation (CD)8(+) T cells are like a double edged sword during chronic viral infections because they not only promote virus elimination but also induce virus-mediated immunopathology. Elevated levels of reactive oxygen species (ROS) have been reported during virus infections. However, the role of ROS in T-cell-mediated immunopathology remains unclear. Here we used the murine lymphocytic choriomeningitis virus to explore the role of ROS during the processes of virus elimination and induction of immunopathology. We found that virus infection led to elevated levels of ROS producing granulocytes and macrophages in virus-infected liver and spleen tissues that were triggered by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Lack of the regulatory subunit p47phox of the NADPH oxidase diminished ROS production in these cells. While CD8(+) T cells exhibited ROS production that was independent of NADPH oxidase expression, survival and T-cell function was elevated in p47phox-deficient (Ncf1(-/-)) mice. In the absence of p47phox, enhanced T-cell immunity promoted virus elimination and blunted corresponding immunopathology. In conclusion, we find that NADPH-mediated production of ROS critically impairs the immune response, impacting elimination of virus and outcome of liver cell damage.

    View details for DOI 10.1038/cdd.2012.167

    View details for PubMedID 23328631

  • Caspase Functions in Cell Death and Disease COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY McIlwain, D. R., Berger, T., Mak, T. W. 2013; 5 (4)

    Abstract

    Caspases are a family of endoproteases that provide critical links in cell regulatory networks controlling inflammation and cell death. The activation of these enzymes is tightly controlled by their production as inactive zymogens that gain catalytic activity following signaling events promoting their aggregation into dimers or macromolecular complexes. Activation of apoptotic caspases results in inactivation or activation of substrates, and the generation of a cascade of signaling events permitting the controlled demolition of cellular components. Activation of inflammatory caspases results in the production of active proinflammatory cytokines and the promotion of innate immune responses to various internal and external insults. Dysregulation of caspases underlies human diseases including cancer and inflammatory disorders, and major efforts to design better therapies for these diseases seek to understand how these enzymes work and how they can be controlled.

    View details for DOI 10.1101/cshperspect.a008656

    View details for Web of Science ID 000317175200008

    View details for PubMedID 23545416

  • Involvement of Toso in activation of monocytes, macrophages, and granulocytes PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Lang, K. S., Lang, P. A., Meryk, A., Pandyra, A. A., Boucher, L., Pozdeev, V. I., Tusche, M. W., Goethert, J. R., Haight, J., Wakeham, A., You-Ten, A. J., McIlwain, D. R., Merches, K., Khairnar, V., Recher, M., Nolan, G. P., Hitoshi, Y., Funkner, P., Navarini, A. A., Verschoor, A., Shaabani, N., Honke, N., Penn, L. Z., Ohashi, P. S., Haeussinger, D., Lee, K., Mak, T. W. 2013; 110 (7): 2593-2598

    Abstract

    Rapid activation of immune responses is necessary for antibacterial defense, but excessive immune activation can result in life-threatening septic shock. Understanding how these processes are balanced may provide novel therapeutic potential in treating inflammatory disease. Fc receptors are crucial for innate immune activation. However, the role of the putative Fc receptor for IgM, known as Toso/Faim3, has to this point been unclear. In this study, we generated Toso-deficient mice and used them to uncover a critical regulatory function of Toso in innate immune activation. Development of innate immune cells was intact in the absence of Toso, but Toso-deficient neutrophils exhibited more reactive oxygen species production and reduced phagocytosis of pathogens compared with controls. Cytokine production was also decreased in Toso(-/-) mice compared with WT animals, rendering them resistant to septic shock induced by lipopolysaccharide. However, Toso(-/-) mice also displayed limited cytokine production after infection with the bacterium Listeria monocytogenes that was correlated with elevated presence of Listeria throughout the body. Accordingly, Toso(-/-) mice succumbed to infections of L. monocytogenes, whereas WT mice successfully eliminated the infection. Taken together, our data reveal Toso to be a unique regulator of innate immune responses during bacterial infection and septic shock.

    View details for DOI 10.1073/pnas.1222264110

    View details for Web of Science ID 000315812800047

    View details for PubMedID 23359703

  • iRHOM2 is a critical pathogenic mediator of inflammatory arthritis JOURNAL OF CLINICAL INVESTIGATION Issuree, P. D., Maretzky, T., McIlwain, D. R., Monette, S., Qing, X., Lang, P. A., Swendeman, S. L., Park-Min, K., Binder, N., Kalliolias, G. D., Yarilina, A., Horiuchi, K., Ivashkiv, L. B., Mak, T. W., Salmon, J. E., Blobel, C. P. 2013; 123 (2): 928-932

    Abstract

    iRHOM2, encoded by the gene Rhbdf2, regulates the maturation of the TNF-? convertase (TACE), which controls shedding of TNF-? and its biological activity in vivo. TACE is a potential target to treat TNF-?-dependent diseases, such as rheumatoid arthritis, but there are concerns about potential side effects, because TACE also protects the skin and intestinal barrier by activating EGFR signaling. Here we report that inactivation of Rhbdf2 allows tissue-specific regulation of TACE by selectively preventing its maturation in immune cells, without affecting its homeostatic functions in other tissues. The related iRHOM1, which is widely expressed, except in hematopoietic cells, supported TACE maturation and shedding of the EGFR ligand TGF-? in Rhbdf2-deficient cells. Remarkably, mice lacking Rhbdf2 were protected from K/BxN inflammatory arthritis to the same extent as mice lacking TACE in myeloid cells or Tnfa-deficient mice. In probing the underlying mechanism, we found that two main drivers of K/BxN arthritis, complement C5a and immune complexes, stimulated iRHOM2/TACE-dependent shedding of TNF-? in mouse and human cells. These data demonstrate that iRHOM2 and myeloid-expressed TACE play a critical role in inflammatory arthritis and indicate that iRHOM2 is a potential therapeutic target for selective inactivation of TACE in myeloid cells.

    View details for DOI 10.1172/JCI66168

    View details for Web of Science ID 000314553600045

    View details for PubMedID 23348744

  • Smg1 is required for embryogenesis and regulates diverse genes via alternative splicing coupled to nonsense-mediated mRNA decay PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA McIlwain, D. R., Pan, Q., Reilly, P. T., Elia, A. J., McCracken, S., Wakeham, A. C., Itie-Youten, A., Blencowe, B. J., Mak, T. W. 2010; 107 (27): 12186-12191

    Abstract

    Smg1 is a PI3K-related kinase (PIKK) associated with multiple cellular functions, including DNA damage responses, telomere maintenance, and nonsense-mediated mRNA decay (NMD). NMD degrades transcripts that harbor premature termination codons (PTCs) as a result of events such as mutation or alternative splicing (AS). Recognition of PTCs during NMD requires the action of the Upstream frameshift protein Upf1, which must first be phosphorylated by Smg1. However, the physiological function of mammalian Smg1 is not known. By using a gene-trap model of Smg1 deficiency, we show that this kinase is essential for mouse embryogenesis such that Smg1 loss is lethal at embryonic day 8.5. High-throughput RNA sequencing (RNA-Seq) of RNA from cells of Smg1-deficient embryos revealed that Smg1 depletion led to pronounced accumulation of PTC-containing splice variant transcripts from approximately 9% of genes predicted to contain AS events capable of eliciting NMD. Among these genes are those involved in splicing itself, as well as genes not previously known to be subject to AS-coupled NMD, including several involved in transcription, intracellular signaling, membrane dynamics, cell death, and metabolism. Our results demonstrate a critical role for Smg1 in early mouse development and link the loss of this NMD factor to major and widespread changes in the mammalian transcriptome.

    View details for DOI 10.1073/pnas.1007336107

    View details for Web of Science ID 000279572100028

    View details for PubMedID 20566848

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