| The Natural Killer T (NKT) cell is a unique T cell population which is featured by expressing a semi-invariant T cell receptor and specifically reacting with CD1d presented glycosphingolipid antigens. After being stimulated by CD1d presented glycolipid antigen, such as alpha-GalCer, the most well known NKT cell ligand, NKT cells exhibit a series of strong responses, initiated by secreting large amount of varied types of cytokines and chemokines in a short time. Through the released cytokines and chemokines, together with other induced responses, NKT cells involve in both innate and adaptive immunities, even with certain regulator role. They function not only as the primary defence line since the rapid responses, but also as an ignition for adaptive immunity due to the reciprocal interactions between NKT cells and dendritic cells. With these unique properties, NKT cells participate in a broad range of immune system activities, or other related physiological processes, which attracted many immunologists and cell biologists into this research area. In this thesis, on the other hand, the work has been focusing on investigating the influence from different ligands, on NKT cell function, by mainly chemical biology methods. A series of novel ligands, or modified known ligands were studied on their particular role on NKT cell function, development and maturation. A pre-clinical drug delivery model was also investigated to find out the effects on NKT cell ligand's in vivo activity.;Chapter 1 provides an overall introduction on NKT cell biology, including the NKT cell function, development and related physiological issue. Especially, it was discussed extended on different NKT cell ligands and the structure mechanism behind glycolipid antigen presenting and NKT TCR recognition processes.;With all the background information, in Chapter 2, a series of NKT cell ligand analogues, which were developed by modifying the sugar moiety of alpha-GalCer, were extensively studied. The relationship between structure modification on ligands and the variation on NKT cell activity was further deciphered.;Chapter 3 documented the efforts on attempting to identify an endogenous NKT ligand, which plays a critical role in NKT cell development and maturation. Based on the knowledge of the only known endogenous ligand, iGb3, a novel ligand was proposed. Its potential to be the endogenous ligand was also evaluated.;In Chapter 4, a commonly used drug delivery system, liposome, was introduced for in vivo delivery of alpha-GalCer to reveal the possible physiological influence on this model ligand. A couple of targeting delivery, or non-targeting alpha-GalCer-liposome formulations were developed and their therapeutic effects were characterized. |
