Immunology, Epigenetics and Metabolism

The immune system is the body’s first line of defense against infection and disease and, as such, plays a central role in detecting and eliminating cancers and other harmful agents, like viruses and bacteria. Sometimes, however, immune defenses break down, allowing infections to take hold, or cancer cells to evade detection and proliferate. Metabolic pathways, which regulate cellular energy and function, are emerging as central players in the immune system’s ability to protect against cancer and infections. Growing evidence also points to disruptions in metabolic pathways as a facilitator of cancers’ ability to thwart the immune system. Understanding how malignant cells and pathogens take advantage of these gaps in anti-tumor immunity has great potential for translation into targeted therapies and anti-cancer vaccines.

To this end, the Krawczyk Laboratory investigates the mechanisms that underlie interactions between the immune system, metabolism and cellular programming with the goal of developing new treatments for cancer, infections, autoimmunity and neuroinflammation. Specifically, they are investigating transcriptional and translational regulation in dendritic and T cells — both specialized immune cell types — and exploring the metabolic profiles of differentially activated dendritic cells in the context of cancer immune surveillance, vaccine development and infection.

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  • 121 peer-reviewed papers published in 2023
  • 62 peer-reviewed papers published in high-impact journals in 2023
  • 55 clinical trials launched to date

Connie Krawczyk, Ph.D.

Associate Professor, Department of Metabolism and Nutritional Programming

Areas of Expertise

Immunology, metabolism, molecular and cell biology

Biography

Connie Krawczyk, Ph.D., is an associate professor at Van Andel Institute and a leader in investigating the links between metabolism, epigenetics and the immune system, with the goal of understanding how they work together in health and disease.

She earned her B.S. with honors in molecular biology and genetics from University of Guelph followed by her Ph.D. in cell and molecular biology from University of Toronto. She then completed postdoctoral fellowships in the labs of Dr. Hao Shen and Dr. Edward Pearce at University of Pennsylvania before taking a position as a senior research biologist at Merck Frosst. In 2011, Dr. Krawczyk was recruited to McGill University as an assistant professor, where her work focused on the molecular mechanisms regulating immune function and the immune system’s role in cancer development. She joined VAI as an associate professor in 2018 as part of its new Metabolic and Nutritional Programming group. She is an active member of several professional societies, including the Society for Leucocyte Biology, the immunoTherapy NeTwork (iTNT) and the Canadian Society for Immunology, and has served as a reviewer for the journals Cell Reports, Cell Metabolism, EMBO Reports, Immunity and Nature Scientific Reports, among others.

Society Memberships

Society for Leucocyte Biology
The immunoTherapy NeTwork (iTNT)
Canadian Society for Immunology

Selected Publications

Luda KM, Longo J, Kitchen-Goosen SM, Duimstra LR, Ma EH, Watson MJ, Oswald BM, Fu Z, Madaj Z, Kupai A, Dickson BM, DeCamp LM, Dahabieh MS, Compton SE, Teis R, Kaymak I, Lau KH, Kelly DP, Puchalska P, Williams KS, Krawczyk CM, Lévesque D, Boisvert FM, Sheldon RD, Rothbart SB, Crawford PA, Jones RG. 2023. Ketolysis drives CD8+ T cell effector function through effects on histone acetylation. Immunity.

Compton SE, Kitchen-Goosen SM, DeCamp LM, Lau KH, Mabvakure, Vos M, Williams KS, Wong KK, Shi X, Rothbart SB, Krawczyk CK, Jones RG. 2023. LKB1 controls inflammatory potential through CRTC2-dependent histone acetylation. Mol Cell 83(11):1872–1886.
*Featured as the cover of Molecular Cell

Zhu B, Wei X, Narasimhan H, Qian W, Zhang R, Cheon IS, Wu Y, Li C, Jones RG, Kaplan MH, Vassallo RA, Braciale TJ, Somerville L, Colca JR, Pandey A, Jackson PEH, Mann BJ, Krawczyk CM, Sturek JM, Sun J. 2023. Inhibition of the mitochondrial pyruvate carrier simultaneously mitigates hyperinflammation and hyperglycemia in COVID-19. Sci Immunol 8(82).

Underwood A, Rasicci DT, Hinds D, Mitchell JT, Zieba JK, Mills J, Arnold NE, Cook TW, Moustaqil M, Gambin Y, Sierecki E, Fontaine F, Vanderweele S, Das AS, Cvammen W, Sirpilla O, Soehnlen X, Bricker K, Alokaili M, Green M, Heeringa S, Wilstermann AM, Freeland TM, Qutob D, Milsted A, Jauch R, Triche Jr. TJ, Krawczyk CM, Bupp CP, Rajasekaran S, Francois M, Prokop JW. 2023. Evolutionary landscape of SOX genes to inform genotype-to-phenotype relationships. Genes 14(1):222.

Liu H, Zhai L, Liu Y, Lu D, Vander Ark A, Yang T*, Krawczyk CM*. (2023). The histone demethylase KDM5C controls female bone mass by promoting energy metabolism in osteoclasts. Sci Adv 9(14).
*Co-corresponding authors

Liu H, Liu Y, Jin SG, Johnson J, Xuan H, Lu D, Li J, Zhai L, Li X, Zhao Y, Liu M, Craig SEL, Floramo JS, Molchanov V, Li J, Li JD, Krawczyk C, Shi X, Pfeifer GP, Yang T. 2023.  TRIM28 secures skeletal stem cell fate during skeletogenesis by silencing neural gene expression and repressing GREM1/AKT/mTOR signaling axis. Cell Rep 42(1):112012.

Zhai L, Krawczyk CM. 2022. Skip the buffet, for SPARC’s sake. Immunity 55(9):1583–1585.

Guak H, Sheldon RD, Beddows I, Vander Ark A, Weiland MJ, Shen H, Jones RG, St-Pierre J, Ma EH, Krawczyk CM. 2022. PGC-1B maintains mitochondrial metabolism and restrains inflammatory gene expression. Sci Rep12:16028.

Zhou W, Hinoue T, Barnes B, Mitchell O, Iqbal W, Lee SM, Foy KK, Lee KH, Moyer EJ, VanderArk A, Koeman JM, Ding W, Kalkat M, Spix NJ, Eagleson B, Pospisilik JA, Szabó PE, Bartolomei M, Vander Schaaf NA, Kang L, Wiseman AK, Jones PA, Krawczyk CM, Adams M, Porecha R, Chen BH, Shen H, Laird PW. 2022. DNA methylation dynamics and dysregulation delineated by high-throughput profiling in the mouse. Cell Genom 2(7):100144.

Cordeiro B, Jeon P, Boukhaled GM, Carrado M, Lapohos O, Roy DG, Williams KS, Jones RG, Gruenheid S, Sagan SM, Krawczyk CM. 2020.MicroRNA-9 fine-tunes dendritic cell function by suppressing negative regulators in a cell-type-specific mannerCell Rep 31(4).

Roy DG*, Chen J*, Mamane V, Ma EH, Muhire BM, Sheldon RD, Shorstova T, Koning R, Johnson RM, Esaulova E, Williams KS, Hayes S, Steadman M, Samborska B, Swain A, Daigneault A, Chubukov V, Roddy TP, Foulkes W, Pospisilik JA, Dourgeois-Daigneualt, Artyomov MN, Witcher M, Krawczyk CM, Larochelle C, Jones RG. 2020. Methionine metabolism shapes helper T helper cell responses through regulation of epigenetic reprogrammingCell Metab 31(2):250–266.
*Co-first authors
Highlighted in a preview in Cell Metabolism

EH Ma, Verway MJ, Johnson RM, Roy DG, Steadman M, Hayes S, Williams KS, Sheldon RD, Samborska B, Kosinski PA, Kim H, Griss T, Faubert B, Condotta SA, Krawczyk CM, DeBerardinis RJ, Marsh K, Richer MJ, Chubukov V, Roddy T, Jones RG. 2019. Metabolic profiling using stable isotope tracing reveals distinct patterns of glucose utilization by physiologically activated CD8+ T cellsImmunity.

Guak H, Al Habyan S, Ma EH, Aldossary H, Al-Masri M, Won SY, Ting T, Fixman ED, Jones RG, McCaffrey LM, Krawczyk CM. 2018. Glycolytic metabolism is essential for CCR7 oligomerization and dendritic cell migrationNat Commun 9(1):2563.

Lindsay BJ, Bonar MM, Costas-Cancelas IN, Hung K, Makarkov AI, Chierzi S, Krawczyk CM, Landry N, Ward BJ, Rouiller I. 2018. Morphological characterization of a plant-made virus-like particle vaccine bearing influenza virus hemagglutinins by electron microscopyVaccine 36(16):2147–2154.

Smith LK, Boukhaled GM, Condotta SA, Mazouz S, Guthmiller JJ, Vijay R, Butler NS, Bruneau J, Shoukry NH, Krawczyk CM, Richer MJ. 2018. Interleukin-10 directly inhibits CD8+ T cell function by enhancing N-glycan brancing to decrease antigen sensitivityImmunity 48(2):299–312.e5.

Dimitrov V, Bouttier M, Boukhaled G, Salehi-Tabar R, Avramescu RG, Memari B, Hasaj B, Lukacs GL, Krawczyk CM, White JH. 2017. Hormonal vitamin D up-regulates tissue-specific PD-L1 and PD-L2 surface glycoprotein expression in humans but not miceJ Biol Chem 292(50):20657–20668.

Wouters MC, Laumont CM, Chen B, Han SJ, Matuszewska K, Potts K, Boudreau JE, Krawczyk CM*. 2017. The Summit for Cancer Immunotherapy (Summit4CI), June 26-29, 2016 Halifax, CanadaCancer Immunol Immunother 66(6):811–818.

Ma EH, Bantug G, Griss T, Condotta S, Johnson RM, Samborska B, Mainolfi N, Suri V, Guak H, Balmer ML, Verway MJ, Raissi TC, Tsui H, Boukhaled G, Henriques da Costa S, Frezza C, Krawczyk CM, Friedman A, Manfredi M, Richer MJ, Hess C, Jones RG. 2017. Serine is an essential metabolite for optimal T cell effector functionCell Metab 25(2):345–357.

Torre S, Polyak MJ, Langlais D, Fodil N, Kennedy JM, Radovanovic I, Berghout J, Leiva-Torres G, Krawczyk CM, Ilangumaran S, Mossman K, Liang C, Knobeloch K-P, Healy LM, Antel J, Arbour N, Pratt A, Majewski J, Lathrop M, Vidal SM, Gros P. 2016. USP15 regulates type I interferon response in vivo and is required for pathogenesis of microbial and autoimmune neuroinflammationNat Immunol 17(12):1479.

Pike KA, Hui C, Krawczyk CM. 2016. Detecting secreted analytes from immune cells: An overview of technologiesMethods Mol Biol 1458:111–124.

Boukhaled GM, Cordeiro B, Deblois G, Dimitrov V, Bailey SD, Holowka T, Domi A, Guak H, Chiu H-HC, Everts B, Pearce EJ, Lupien M, White JH, Krawczyk CM. 2016. The transcriptional repressor Polycomb group factor 6, PCGF6, negatively regulates dendritic cell activation and promotes quiescenceCell Rep 16:1829–1837.

Boudreau JE, Wouters MC, Krawczyk CM. 2016. 8th Annual Canadian Cancer Immunotherapy Consortium (CCIC) Symposium 2015–May 20-22, Vancouver, CanadaCancer Immunol Immunother 65(2):235–241.

Van Den Ham KM, Shio MT, Rainone A, Fournier S, Krawczyk CM, M Olivier. 2015. Iron prevents the development of experimental cerebral malaria by attenuating CXCR3-mediated T cell chemotaxisPLoS One 10(3):e0118451.

Blagih J, Coulombe F, Vincent EE, Dupuy F, Galicia-Vázquez G, Yurchenko E, Raissi TC, van der Windt GJ, Viollet B, Pearce EL, Pelletier J, Piccirillo CA, Krawczyk CM, Divangahi M, Jones RG. 2015. The energy sensor AMPK regulates T cell metabolic adaptation and effector responses in vivoImmunity. 42(1):41–54.

Contreras I, Estrada JA, Guak H, Martel C, Borjian A, Ralph B, Shio MT, Fournier S, Krawczyk CM, M Olivier. 2014. Impact of Leishmania mexicana infection on dendritic cell signaling and functionsPLoS Negl Trop Dis 8(9):e3202.

Blagih, J, Krawczyk CM, RG Jones. 2012. LKB1 and AMPK: central regulators of lymphocyte metabolism and functionImmunol Rev 249(1):59–71.

Gallant M, Beaulieu C, Berthelette C, Colucci J, Crackower MA, Dalton C, Denis D, Ducharme Y, Friesen RW, Guay D, Gervais FG, Hamel M, Houle R, Krawczyk CM, Kosjek B, Lau S, Leblanc Y, Lee EE, Levesque JF, Mellon C, Molinaro C, Mullet W, O’Neill GP, O’Shea P, Sawyer N, Sillaots S, Simard D, Slipetz D, Stocco R, Sørensen D, Truong VL, Wong E, Wu J, Zaghdane H, Wang Z. 2011. Discovery of MK-7246, a selective CRTH2 antagonist for the treatment of respiratory diseasesBioorg Med Chem Lett 21(1):288–293.

Gervais FG, Sawyer N, Stocco R, Hamel M, Krawczyk CM, Sillaots S, Denis D, Wong E, Wang Z, Gallant M, Abraham WM, Slipetz D, Crackower MA, O’Neill GP. 2011. Pharmacological characterization of MK-7246, a potent and selective CRTH2 antagonistMol Pharmacol 79(1):69–76.

Krawczyk CM, Holowka T, Sun J, Blagih J, Amiel E, DeBerardinis R, Cross JR, Jung E Thompson CB, Jones RG, EJ Pearce. 2010. Toll-like receptor induced changes in glycolytic metabolism regulate dendritic cell activationBlood 115(23):4742–4749.

Carvalho L, Sun J, Kane C, Marshall F, Krawczyk CM, EJ Pearce. 2009. Review series on helminths, immune modulation and the hygiene hypothesis: mechanisms underlying helminth modulation of dendritic cell functionImmunology 126(1):28–34.

Taylor JJ, Krawczyk CM, Mohrs, M, EJ Pearce. 2009. Th2 cell hyporesponsiveness during chronic murine schistosomiasis is cell-intrinsic and linked to GRAIL expressionJ Clin Invest 119(4):1019–10128.

Krawczyk CM, Sun J, EJ Pearce. 2008. Th2 differentiation is unaffected by Jagged2 expression on dendritic cellsJ Immunol 180(12):7931–7937.

Sun J, Krawczyk CM, EJ Pearce. 2008. Suppression of Th2 cell development by Notch ligands Delta1 and Delta4J Immunol 180(3):1655–1661.

Jones RG, Bui T, White C, Madesh M, Krawczyk CM, Lindsten T, Kubek S, Frauwirth KA, Wang LY, Hawkins BJ, Conway SJ, Roderick HL, Bootman MD, Shen H, Fosket JK, CB Thompson. 2007. Bax and Bak regulate T cell proliferation through control of ER Ca2+ homeostasisImmunity 27(2):268–280.

Krawczyk CM, Shen, H, EJ Pearce. 2007. Memory CD4 cells enhance CD8 primary responsesInfect Immun 75(7):3556–3560.

Krawczyk CM, Shen H, EJ Pearce. 2007. Functional plasticity in T helper responsesJ Immunol 178(7):4080–4088.

Jones RG, Saibil SD, Pun JM, Elford AR, Bonnard M, Pellegrini M, Arya S, Parsons ME, Krawczyk CM, Gerondakis S, Yeh WC, Woodgett JR, Boothby MR, PS Ohashi. 2005. NFkappaB couples protein kinase B/Akt signaling to distinct survival pathways and the regulation of lymphocyte homeostasis in vivo. J Immunol 175(6): 3790–3799.

Krawczyk CM, Jones RG, Atfield A, Bachmaier K, Arya S, Odermatt B, Ohashi PS, JM Penninger. 2005. Differential control of CD28-regulated in vivo immunity by the E3 ligase Cbl-bJ Immunol 174(3):1472–1478.

Jeon MS, Atfield A, Venuprasad K, Krawczyk CM, Sarao R, Elly C, Yang C, Arya S, Bachmaier K, Su L, Bouchard D, Jones R, Gronski M, Ohashi P, Wada T, Bloom D, Fathman CG, Liu YC, JM Penninger. 2004. Essential role of the E3 ubiquitin ligase Cbl-b in T cell anergy inductionImmunity (2):167–177.

Pearce EL, Mullen AC, Martins GA, Krawczyk CM, Hutchins AS, Zediak VP, Banica M, DiCioccio CB, Gross DA, Mao CA, Shen H, Cereb N, Yang SY, Lindsten T, Rossant J, Hunter CA, SL Reiner. 2003. Control of effector CD8+ T cell function by the transcription factor EomesoderminScience 302(5647):1041–1043.

Griffiths EK, Sanchez O, Mill P, Krawczyk CM, Hojilla CV, Rubin E, Nau MN, Khokha R, Lipkowitz S, Hui C-C, JM Penninger. 2003. Cbl-3-deficient mice exhibit normal epithelial developmentMol Cell Biol  (21):7708–7718.

Hara H, Wada T, Bakal C, Kozieradzki I, S Suzuki S, Suzuki N, Nghiem M, Griffiths EK, Krawczyk CM, Bauer B, D’Acquisto F, Ghosh S, Yeh WC, Baier G, Rottapel R, and JM Penninger. 2003. The MAGUK family protein CARD11 is essential for lymphocyte activationImmunity (6):763–775.

Jones RG, Elford AR, Parsons MJ, Wu L, Krawczyk CM, Yeh WC, Hakem R, Rottapel R, Woodgett JR, and PS Ohashi. 2002. CD28-dependent activation of protein kinase B/Akt blocks Fas-mediated apoptosis by preventing death-inducing signaling complex assemblyJ Exp Med 196(3):335–348.

Krawczyk CM, Oliveira-dos-Santos A, Griffiths E, Sasaki T, Ohashi PS, Snapper S, Alt F, JM Penninger. 2002. Vav1 controls integrin clustering and MHC/peptide-specific cell adhesion to antigen presenting cellsImmunity (3):331–343.

Griffiths E, Krawczyk CM, Kong Y-Y, Raab M, Hyduk SJ, Bouchard D, Chan VS, Kozieradski I, Oliveira-dos-Santos A, Wakeham A, Mak TW, Ohashi PS, Cybulsky MI, Rudd CE, JM Penninger. 2001. Positive regulation of T cell activation and integrin adhesion by the adapter Fyb/SlapScience 293(5538):2260–2263.

Irie-Sasaki J, Sasaki T, Matsumoto W, Opavsky A, Cheng M, Welstead G, Griffiths E, Krawczyk CM, Richardson CD, Aitken K, Iscove N, Koretzky G, Johnson P, Liu P, Rothstein DM, JM Penninger. 2001. CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalingNature 409(6818):349–354.

Krawczyk CM, JM Penninger. 2001. Molecular controls of antigen receptor clustering and autoimmunityTrends Cell Biol 11(5): 212–220.

Krawczyk CM, JM Penninger. 2001. Molecular motors involved in T cell receptor clusterings. J Leukoc Biol 69(3):317–330.

Krawczyk CM, Bachmaier K, Sasaki T, Jones RG, Snapper SB, Bouchard D, Kozieradzki I, Ohashi PS, Alt FW, JM Penninger. 2000. Cbl-b is a negative regulator of receptor clustering and raft aggregation in T cellsImmunity 13(4):463–473.

Shin M-K, Hwang U-W, Kim W, Wright A-D, Krawczyk CM, DH Lynn. 2000. Phylogenetic position of the ciliate Phacodinium (Order Phacodiniida) and Protocruzia (Subclass Protocruziidia) and systematics of the Spirotrich ciliates examined by small subunit ribosomal RNA gene sequencesEurop J Protistol 36:293–302.

Bachmaier K, Krawczyk CM, Kozieradzki I, Kong YY, Sasaki T, Oliveira-dos-Santos A, Mariathasan S, Bouchard D, Wakeham A, Itie A, Le J, Ohashi PS, Sarosi I, Nishina H, Lipkowitz S, JM Penninger. 2000. Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b. Nature 403(6766):211–216.

Bachmann MF, Nitschke L, Krawczyk CM, Tedford K, Ohashi PS, Fischer KD, JM Penninger. 1999. The guanine-nucleotide exchange factor Vav is a crucial regulator of B cell receptor activation and B cell responses to nonrepetitive antigensJ Immunol 163(1):137–142.

Ebenezer Asiedu

Ph.D. Candidate, VAI Graduate School

Bryn Couturier

Student Intern

Paula Davidson

Senior Research Technician, Krawczyk Laboratory

Cameron Forton

Ph.D. Candidate, VAI Graduate School

Hyo-Jun Kim, Ph.D.

Postdoctoral Fellow, Krawczyk Laboratory

Cameron Lee

Assistant Research Technician, Department of Metabolism and Nutritional Programming

Alexandra VanderArk, M.S.

Laboratory Manager, Department of Metabolism and Nutritional Programming

Jeanie Wedberg

Senior Administrative Assistant II

Matthew Weiland, M.S.

FACS Specialist, Department of Metabolism and Nutritional Programming

Lukai Zhai, Ph.D.

Postdoctoral Fellow, Krawczyk Laboratory

Histone H3 lysine 4 demethylase KDM5C/D functions in dendritic cells

Past Lab Members

Mario Corrado

M.Sc. Student

Paula Davidson, M.S.

Research Associate

Batsi Mabvakure, Ph.D.

Bioinformatics Research Scientist, Krawczyk Laboratory

Brejnev Muhire, Ph.D.

Bioinformatics Research Scientist

Christina Straham

Van Andel Institute Graduate School Student