Development of novel agonists for human iNKT cells

Authors

• A Hara
• J DiSapio
• M Coombs
• G Khayrullina
• V Joshi
• M Watowich
• M Watanabe
• K Smith
• MM Alam
• H Kim
• N Malik
• E Steffke
• L Latifi
• J Hancock
• J Gumperz
• M Gilbert
• A Howell
• M Terabe

Abstract

Invariant natural killer T (iNKT) cells are CD1d-restricted T cells expressing a semi-invariant T cell receptor (TCR) that recognizes lipid antigens and is involved in anti-cancer immune response. A unique characteristic of iNKT cells is that there is a large spectrum of antigen structures that a single TCR could recognize. Studies of α-galactosylceramide (α-GalCer) analogs, prototype iNKT cell antigens, have shown that differences in the structures of antigens significantly alter the activities of mouse iNKT cells. However, human iNKT cells have been much less studied. We investigated the antigenic activity of novel sulfatide-based lipids for human iNKT cells. Eight new sulfatide analogs were synthesized with fluorobenzene at the end of acyl chains and three sphingoid base structures. The activation of iNKT cells from peripheral blood mononuclear cells (PBMCs) was measured by the expression of CD69 and CD25. This activation of iNKT cells was seen in a CD1d-dependent manner. The sulfatide analogs induced the production of multiple cytokines, particularly high levels of IL-2, while α-GalCer did not. The lack of induction of IL-2 by α-GalCer was confirmed by blocking CD25 to prevent consumption of IL-2 by activated iNKT cells. These data suggested that the sulfatide analogs may have an advantage over α-GalCer to better support NKT/T cell proliferation, particularly when used as a vaccine adjuvant. The novel agonist for human iNKT cells may be useful in the development of vaccines that can be successfully used in humans as effective adjuvants.

Scientific Focus Area: Immunology

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