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

Abstract

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.