The structure-function relationships of sulfatide analogs for the activity of human iNKT cells

Authors

• A Hara
• J DiSapio
• M Coombs
• G Khayrullina
• V Joshi
• M Watowich
• M Watanabe
• K Smith
• J Gumperz
• M Gilbert
• A Howell
• M Terabe

Abstract

Invariant natural killer T (iNKT) cells are an unconventional T cell subset expressing a semi-invariant T cell receptor (TCR) that recognizes lipid antigens presented by the monomorphic MHC I-like molecule CD1d. Studies of α-galactosylceramide (α-GalCer) analogs, prototype iNKT cell antigens, have shown that differences in the structures of glycolipid antigens can significantly alter the activities of iNKT cells. However, recent studies suggested that structure-function relationships provided by analysis of iNKT cell recognition of α-GalCer analogs are not necessarily applicable to other glycolipid antigens. This study investigates the structure-function relationships of a self-glycolipid antigen, sulfatide, for the activation of human iNKT cells. Eight new sulfatide analogs with structures similar to 7DW8-5, a glycolipid 100-fold more potent in stimulating iNKT cells than α-GalCer, have been synthesized. First, we examined the recognition of the sulfatide analogs by the TCR of iNKT cells by creating CD1d-tetramers loaded with sulfatide analogs and used them to stain iNKT cells. The results showed that the staining properties of CD1d-tetramers differ depending on the acyl chain structure of the sulfatide analog loaded. Next, we will examine the stimulatory properties of the analogs against a human iNKT cell line in vitro. Once we have identified analogs that can stimulate human iNKT cell lines, we plan to test their antigenicity using ex vivo human iNKT cells. The information obtained from this study could help design new agonistic lipid antigens for human iNKT cells, creating a potential therapeutic strategy to augment an anti-cancer immune response.

Scientific Focus Area: Immunology

This page was last updated on Monday, September 25, 2023