Glycolipids that Elicit IFN-¦Ã-Biased Responses from Natural Killer T Cells

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• 作者：Aaron  ; J. Tyznik¹ ; ⁶ ; Elisa Farber³ ; ⁶ ; Enrico Girardi² ; Alysia Birkholz¹ ; ² ; Yali Li² ; Sampada Chitale³ ; Regina So³ ; Pooja Arora⁴ ; Archana Khurana¹ ; Jing Wang² ; Steven  ; A. Porcelli⁵ ; Dirk  ; M. Zajonc² ; ⁷ ; ^{dzajonc@liai.org} ; Mitchell Kronenberg¹ ; ⁷ ; ^{mitch@liai.org} ; Amy  ; R. Howell³ ; ⁷ ; ^{amy.howell@uconn.edu}
• 刊名：Chemistry & Biology
• 出版年：2011
• 出版时间：23 December 2011
• 年：2011
• 卷：18
• 期：12
• 页码：1620-1630
• 全文大小：1236 K

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Summary

Natural killer T (NKT) cells recognize glycolipids presented by CD1d. The first antigen described, ¦Á-galactosyl ceramide (¦ÁGalCer), is a potential anticancer agent whose activity depends upon IFN-¦Ã secretion. We report two analogs of ¦ÁGalCer based on a naturally occurring glycosphingolipid, plakoside A. These compounds induce enhanced IFN-¦Ã that correlates with detergent-resistant binding to CD1d and an increased stability of the lipid-CD1d complexes on antigen-presenting cells. Structural analysis on one of the analogs indicates that it is more deeply bound inside the CD1d groove, suggesting tighter lipid-CD1d interactions. To our knowledge, this is the first example in which structural information provides an explanation for the increased lipid-CD1d stability, likely responsible for the Th1 bias. We provide insights into the mechanism of IFN-¦Ã-inducing compounds, and because our compounds activate human NKT cells, they could have therapeutic utility.