Abstract

Natural killer T (NKT) cells are a subset of T cells that modify a variety of immune responses. NKT cells recognize glycolipid antigen presented by a molecule called CD1d, a nonclassical antigen-presenting molecule. The best known subset of CD1d-dependent NKT cells expresses an invariant T cell receptor Vα (TCR-α) chain. These are referred to as type I or invariant NKT (iNKT) cells. When stimulated by a glycolipid, NKT cells rapidly release large amounts of cytokines. Cytokines released by NKT cells can induce either Th1 or Th2 responses. Th1 cytokines are effective in regulating bacterial, parasitic, and viral infections. But Th1 responses are also involved in some autoimmune diseases, such as type 1 diabetes, lupus, rheumatoid arthritis, and allergen-induced asthma. Th2 cytokines can attenuate proinflammatory Th1 responses and therefore prevent some autoimmune diseases. Lysosomal processing and CD1d loading is very important in regulating the stimulatory properties of antigens. Analogs of KRN7000, with small molecules appended on C6” position of the galactose portion, do not significantly change stimulation of NKT cells. The question is if the substitution at this position would influence the lysosomal processing. Two sets of mono- and disaccharides with and without substitution at C6” position were prepared and evaluated the NKT cell stimulatory properties. The substitution at the C6” position of the sugar moiety of glycolipids do not significantly impact the stimulatory properties of glycolipids and their processing in lysosome. Small changes at C6” are well tolerated. A double bond in the acyl chain and modification of the C6” functional group helped the glycolipid loading into CD1d and NKT cells stimulation. PBS57 is 100 times more active than KRN 7000 in stimulation of NKT cells responses in vitro and in vivo. This improvement is probably due to increasing solubility and improving binding ability with the CD1d.

Degree

PhD

College and Department

Physical and Mathematical Sciences; Chemistry and Biochemistry

Rights

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