Natural Killer T cells (NKT) are a hybrid cell type of NK cells and T cells, but are activated only by antigenic stimulation. NKT cells bridge innate and adaptive immunity through recognition of lipid ligands from both microbial and self origins. Endogenous NKT ligands, which are metabolism products of self lipids, are involved in immuno-pathology of infectious diseases, auto-immune diseases and cancer. However, molecular identification of these endogenous ligands has been difficult due to technical barriers. Recently, we found that NB-DGJ, a drug which inhibits glucosylceramide synthase, completely abolishes the development of NKT cells. More importantly, we identified isoglobotrihexosylceramide, one of the target glycosphingolipids being inhibited by NB-DGJ, as the first known natural ligand for NKT cells. However, iGb3 synthase knockout mice showed no defect in NKT cell development and function, indicating that other GSL and/or non-GSL ligands exist. Continued development of glycolipidomics assays, assisted by ion trap mass spectrometry technology, enhances our ability to further understand these mechanisms and identify new ligands. In this project, we will test the hypothesis that at least one endogenous ligand of NKT cells, other than iGb3, exists and is responsible for the development and activation of NKT cells. Identifying one or more endogenous ligands may permit new approaches to regulating the function of NKT cells in disease settings such as cancer and autoimmune diseases.
The specific aims of this project are: 1) Determine the identities of stimulatory GSL and/or non-GSL antigens by biochemical fractionation and analysis;2) Utilize the genetic pathways to identify potential endogenous NKT ligands. The molecular identification of natural ligands for NKT cells is not only an urgent, but also a challenging task in the field of innate immunity. Although the search for these ligands has lasted more than a decade, they remain elusive. We therefore have chosen a combined approach of biochemical fractionation/characterization and genetic knockdown of key enzymes to help bring this search to fruition. The completion of human genome project and the advancement of mass spectrometry technology provide the framework to move the field of lipid antigens forward and potentially permit the identification of new therapeutic approaches to some of the most complex immune-related diseases. More important, this project will provide early insights into cellular lipidomics studies, with a specific focus on the important immunological functions of glycolipids. More than 10% of the genes in the human genome are used for lipid metabolism;thus, knowledge and experience gained in this project may have profound implications on studies of functional lipidomics, an important but little-understood area compared with proteomics and genomics.
NKT lymphocytes represent an essential component of innate immunity, that can jump start the adaptive immune responses and regulate the immune outcome. Understanding the identities of the natural ligands for NKT cells is a prerequisite to study the regulation of NKT cells in patho-physiological conditions. Our long-term goal is to elucidate the molecular mechanisms of the biosynthesis pathways of natural ligands for NKT cells, and to identify druggable targets of regulation. The important clinical benefit of this project is 1) novel therapeutic application of lipid-metabolism-interfering drugs in immuno-regulation of NKT cells;2) identification of new natural NKT ligands as targets for immuno-therapy of autoimmune diseases and cancer.
|Qu, Jin; Yu, Hongtao; Li, Fenge et al. (2016) Molecular basis of antibody binding to mucin glycopeptides in lung cancer. Int J Oncol 48:587-94|
|DeLyria, Elizabeth S; Zhou, Dapeng; Lee, Jun Soo et al. (2015) Sublingual injection of microparticles containing glycolipid ligands for NKT cells and subunit vaccines induces antibody responses in oral cavity. Carbohydr Res 405:87-92|
|Zhu, Haoxiang; Zhang, Yongmei; Liu, Hongyan et al. (2015) Preserved Function of Circulating Invariant Natural Killer T Cells in Patients With Chronic Hepatitis B Virus Infection. Medicine (Baltimore) 94:e961|
|Zhu, Jian; Wang, Yanping; Yu, Yunhui et al. (2014) Aberrant fucosylation of glycosphingolipids in human hepatocellular carcinoma tissues. Liver Int 34:147-60|
|Tahiri, Fatima; Li, Yunsen; Hawke, David et al. (2013) Lack of iGb3 and Isoglobo-Series Glycosphingolipids in Pig Organs Used for Xenotransplantation: Implications for Natural Killer T-Cell Biology. J Carbohydr Chem 32:44-67|
|Yin, Alexandra Bili; Hawke, David; Zhou, Dapeng (2013) Mass spectrometric analysis of glycosphingolipid antigens. J Vis Exp :|
|Wang, Zheng; Wen, Lijun; Ma, Xiao et al. (2012) High expression of lactotriaosylceramide, a differentiation-associated glycosphingolipid, in the bone marrow of acute myeloid leukemia patients. Glycobiology 22:930-8|
|Chung, Yeonseok; Lee, Young-Hee; Zhang, Yongliang et al. (2012) T cells and T cell tumors efficiently generate antigen-specific cytotoxic T cell immunity when modified with an NKT ligand. Oncoimmunology 1:141-151|
|Zhou, Xiao-Fei; Yu, Jiayi; Chang, Mikyoung et al. (2012) TRIM28 mediates chromatin modifications at the TCRÎ± enhancer and regulates the development of T and natural killer T cells. Proc Natl Acad Sci U S A 109:20083-8|
|Song, Wei; Delyria, Elizabeth S; Chen, Jieqing et al. (2012) MUC1 glycopeptide epitopes predicted by computational glycomics. Int J Oncol 41:1977-84|
Showing the most recent 10 out of 19 publications