Activation of Natural Killer T cells and Dendritic cells with Caulobacter crescentus: Implications for developing tumour immunity

  • Author / Creator
    Loo, Eric Wah-Leck
  • Cancer remains a leading cause of mortality worldwide. Efforts to develop immuno-therapies to control the growth of cancer, while limiting host cell damage, have focused on targeting specific tumour associated antigens. These treatments have yielded some clinical success however; the limited targeting of tumour antigens potentially allows the tumour to escape the treatment through antigen mutation or down-regulation of expression. In this thesis, we focused on the ability of non-pathogenic, Gram negative bacteria, Caulobacter crescentus to stimulate innate immunity to generate a response capable of controlling the growth of syngeneic tumours. We evaluated the ability of C.crescentus to activate natural killer T cells (NKT) and dendritic cells (DCs) as both cell populations affect the continued development of the inflammatory process. The activation of NKT cells was determined using Ja18-/- or CD1d-/- mice which lacked either a subset or all CD1d-dependent NKT cells respectively. NKT cell activation was determined through measurements of the early activation marker CD69 and various cytokines such as IFN-gamma. DC activation by C.crescentus was characterized through observations made with bone marrow derived DCs and their ability to express co-stimulatory markers such as CD40, CD54, CD80, and CD86. The interaction of C.crescentus stimulated NKT cells and DCs revealed that C. crescentus stimulated NKT cells through a contact dependent pathway which may not require the recognition of the CD1d-lipid complex. Additionally, the interaction of C.crescentus activated NKT cells and DCs resulted in an enhanced expression of factors that are known promoters of Th1 cellular immunity such as IL-12p70 and CD40. The immunity stimulated by C.crescentus was shown to slow the growth of EL4 subcutaneous tumours. Interestingly, through the course of our studies we revealed a role for a subset of NKT cells, type 1 NKT cells, absent in Ja18-/- mice to support the growth of syngeneic tumours. We found that Ja18-/- mice bone marrow derived DCs expressed increased Th1 promoting factors. This novel observation indicates a role for NKT cells in the development and maintenance of DC homeostasis in the wild-type animal.

  • Subjects / Keywords
  • Graduation date
  • Type of Item
  • Degree
    Doctor of Philosophy
  • DOI
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
  • Institution
    University of Alberta
  • Degree level
  • Department
    • Department of Surgery
  • Specialization
    • Experimental Surgery
  • Supervisor / co-supervisor and their department(s)
    • Agrawal, Babita (Surgery)
  • Examining committee members and their departments
    • Kane, Kevin (Medical Microbiology and Immunology)
    • Rayat, Gina (Surgery)
    • Anderson, Colin (Surgery)
    • Agrawal, Babita (Surgery)
    • Singh, Bhagirath (University of Western Ontario, Microbiology and Immunology)