Research Summary

The innate immune system is an evolutionarily ancient system that depends on key sentinel cells such as dendritic cells (DCs), macrophages, neutrophils and mast cells to provide the first line of defense against pathogenic microbes. Signalling defects within the innate immune system may result in immunodeficiency characterized by the inability to clear infections, while excessive or inappropriate activation of innate immune cells, can lead to devastating acute or chronic inflammatory diseases such as sepsis, rheumatoid arthritis, asthma, COPD and inflammatory bowel disease. The DC lineage is critical for organising appropriate immune responses to pathogens and tumours and is also essential for maintaining immunological tolerance to self-antigens and for limiting potentially self-destructive immune responses. The prospect of employing DCs to combat infectious disease, in tumour immunotherapy, and in the treatment of autoimmune disease is encouraging, however, an understanding of DC subset function and the intricacies of signalling pathways regulating DC development and activity is only beginning to emerge.

The long-term goal of the laboratory is to identify the key genes and cellular pathways that guide dendritic cell lineage choice and dendritic cell function. We are particularly interested in the role of tyrosine kinase/phosphatase-regulated signalling pathways that control signalling thresholds important for the development and function of DCs and other phagocyte populations. Our work utilizes mouse models in which the levels and activities of key signaling molecules have been manipulated allowing us to delineate the roles of particular genes or signalling pathways in mammalian dendritic cell biology and in innate/adaptive immunity at the whole animal level. We are using these mouse models to explore the relationship between alterations in DC development/function and host responses to tumours and bacterial or viral pathogens. Ultimately, this research program will lead to the identification of critical proteins and pathways that may become targets of future therapeutic strategies to either augment host-pathogen/tumour responses or alleviate pathological immune responses.

Teaching

B.Sc. Simon Fraser University, 1990
Ph.D., The Biomedical Research Centre (UBC, Genetics, 1996)
Postdoctoral fellow, The Ludwig Institute for Cancer Research, Australia, 1998-2006

Publications

Selected publications

  1. Roberts ME, Bishop JL, Fan X, Beer JL, Kum WW, Krebs DL, Huang M, Gill N, Priatel JJ, Finlay BB, Harder KW. Lyn Deficiency Leads to Increased Microbiota-Dependent Intestinal Inflammation and Susceptibility to Enteric Pathogens. J Immunol. 2014 Oct 22. pii: 1302832. [Epub ahead of print]
  2. Bishop JL, Roberts ME, Beer JL, Huang M, Chehal MK, Fan X, Fouser LA, Ma HL, Bacani JT, Harder KW. Lyn activity protects mice from DSS colitis and regulates the production of IL-22 from innate lymphoid cells. Mucosal Immunol. 2014 Mar;7(2):405-16.
  3. Sio A, Chehal MK, Tsai K, Fan X, Roberts ME, Nelson BH, Grembecka J, Cierpicki T, Krebs DL, Harder KW. Dysregulated hematopoiesis caused by mammary cancer is associated with epigenetic changes and hox gene expression in hematopoietic cells. Cancer Res. 2013 Oct 1;73(19):5892-904.
  4. Krebs DL, Chehal MK, Sio A, Huntington ND, Da ML, Ziltener P, Inglese M, Kountouri N, Priatel JJ, Jones J, Tarlinton DM, Anderson GP, Hibbs ML, Harder KW. Lyn-dependent signaling regulates the innate immune response by controlling dendritic cell activation of NK cells. J Immunol. 2012 May 15;188(10):5094-105.
  5. Harder KW, Quilici C, Naik E, Inglese M, Kountouri N, Turner A, Zlatic K, Tarlinton DM, Hibbs ML. Perturbed myelo/erythropoiesis in Lyn-deficient mice is similar to that in mice lacking the inhibitory phosphatases SHP-1 and SHIP-1. Blood. 2004 Dec 15;104(13):3901-10.
  6. Harder KW, Parsons LM, Armes J, Evans N, Kountouri N, Clark R, Quilici C, Grail D, Hodgson GS, Dunn AR, Hibbs ML. Gain- and loss-of-function Lyn mutant mice define a critical inhibitory role for Lyn in the myeloid lineage. Immunity. 2001 Oct;15(4):603-15. (Featured Article)
  7. Xu Y, Harder KW, Huntington ND, Hibbs ML, Tarlinton DM. Lyn tyrosine kinase: accentuating the positive and the negative. Immunity. 2005 Jan;22(1):9-18. Review.
Office Phone
6048274349
Office
3509