Structure-Activity Studies of Glycosphingolipids as Antigens of Natural Killer T Cells Structure-Activity Studies of Glycosphingolipids as Antigens of Natural Killer T Cells
To understand the structure-activity relationship between GSLs and NKT cell activity and the requirements for intracellular processing of antigens, analogs of the model compound alphaGalCer (KRN-7000) have been synthesized. These include fluorophore-appended 6ï¿½-amino-alpha-galactosylceramides and N-alkenoyl GSLs, such as PBS-57, a potent alphaGalCer surrogate useful in NKT cell stimulation studies. A nonantigenic beta-C-galactosylceramide has also been prepared as an inhibitor of these innate lymphocytes.
To probe the potential for using NKT cells to bias the immune system between the proinflammatory TH1 response or the immunomodulatory TH2 mode, versions of alphaGalCer with shortened ceramides have been created. One of these truncated analogs, PBS-25, has successfully been cocrystallized with CD1d and the binary complex structure solved by X-ray crystallography.
Synthetic glycosphingolipids derived from Novosphingobium capsulatum and Sphingomonas paucimobilis have also been made. In assays with classical Valpha14i/Valpha24i NKT cell lines, these Gram-negative bacterial antigens were recognized directly and specifically by host immune systems through CD1d-restriction, unlike GSL-deficient microbes (e.g., Salmonella typhimurium). A search for other GSL-bearing alpha-proteobacteria led to the discovery of another natural glycosphingolipid, an N-alkenoylphytosphingoid-alpha-galactoside, isolated from the outer membrane of Ehrlichia muris.
School:Brigham Young University
School Location:USA - Utah
Source Type:Master's Thesis
Keywords:glycosphingolipid gsl natural killer t cell nkt alpha galactosylceramide ceramide cd1d glycolipid sphingomonas novosphingobium capsulatum paucimobilis ehrlichia muris pbs 25 57 dendritic dc c glycoside agalcer krn 7000 th1 th2 interferon gamma interleukin 4 synthesis structure activity relationship
Date of Publication:07/25/2006