Research Area: Immunology, Molecular and Cell Biology
The Krawczyk lab studies the molecular mechanisms regulating immune cell function, focused on dendritic cell (DC) and T cell activation, differentiation and function. The specific molecular mechanisms that we are interrogating can be broadly grouped into mechanisms that regulate gene expression (both transcription and translation) those which regulate cellular metabolism. We study these mechanisms in the context of both discovery research and health and disease including Leishmania infection, cancer immune-surveillance and vaccine development.
1. Gene Expression Programs in DCs
Transcriptional Regulation: We are studying the transcriptional repressor Mel- Bmi-like Ring finger protein (MBLR) and its role in regulating DC function. We first identified MBLR as a gene that was down-regulated upon activation of DCs. Since polycomb proteins are transcriptional repressors we hypothesized that MBLR regulates DC activation and function.
We are also studying a group of transcriptional activators, the Notch family proteins. DCs express both Notch ligands and receptors and their role in DC biology is not well understood. It is thought that DCs deliver specific signals to T cells via the differential expression of Notch ligands DLL-1/4 and Jag1/2, however we have found that both Notch ligands and receptors regulate DC biology. Current studies aim to decipher the roles of Notch receptors and ligands in regulating DC activation, function and ability to communicate to T cells.
Translational Regulation: Since DCs are poised at the cellular level to respond to environmental threats, we hypothesize that DCs are also poised at the molecular level to acquire different activation phenotypes. mRNA expression analysis has revealed differences between differentially activated DCs however, the differences have been underwhelming. We hypothesize that there is an additional layer of regulation at the level of translation that facilitates immediate and differential activation of DCs. MicroRNAs have been identified as key regulators of translation allowing for dynamic regulation of gene expression. We are evaluating the role of specific microRNAs to regulate differential DC activation and to control gene expression programs in DCs.
2. Metabolic Pathways
Metabolic pathways regulate cellular energy and biosynthetic pathways, and are increasingly shown to regulate cellular function. A main focus of the lab is to study the role that cellular metabolism plays in DC activation and function. We are currently examining the metabolic profile of differentially activated DCs, and are beginning to determine whether differential use of metabolic pathways regulates their function.
1. 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. The energy sensor AMPK regulates T cell metabolic adaptation and effector responses in vivo. Immunity. 2015 Jan 20;42(1):41-54
2. Contreras I, Estrada JA, Guak H, Martel C, Borjian A, Ralph B, Shio MT, Fournier S, Krawczyk CM, and M. Olivier. PLoS Negl Trop Dis. Impact of Leishmania mexicana Infection on Dendritic Cell Signaling and Functions. PLoS Negl Trop Dis. 2014 Sep 25;8(9):e3202.
3. Blagih, J, Krawczyk, CM and RG Jones. LKB1 and AMPK: central regulators of lymphocyte metabolism and function. Immunol Rev. 2012 Sep;249(1):59-71
4. Krawczyk CM, Holowka T, Sun J, Blagih J, Amiel E, DeBerardinis R, Cross JR, Jung E Thompson CB, Jones RG, and EJ Pearce. Toll-like receptor induced changes in glycolytic metabolism regulate dendritic cell activation. Blood. 2010. 115(23):4742-9.
5. Krawczyk CM, Sun J and EJ Pearce. Th2 differentiation is unaffected by Jagged2 expression on Dendritic Cells. J Immunol. 2008.180(12): 7931-7.
6. Sun J, Krawczyk CM and EJ Pearce. Suppression of Th2 cell development by Notch ligands Delta1 and Delta4. J Immunol. 2008. 180(3): 1655-61.
7. Krawczyk CM, Shen, H and EJ Pearce. Memory CD4 cells enhance CD8 primary responses. 2007. Infect. Immun. 75(7): 3556-60.
8. Krawczyk CM, Shen, H and EJ Pearce. Functional plasticity in T helper responses. 2007. J Immunol. 2007. 178(7): 4080-8.