Natural killer t cell activation by CD1d glycolipid ligand based on “anchoring effect” of polar groups in lipid component

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Natural killer t cell activation by CD1d glycolipid ligand based on “anchoring effect” of polar groups in lipid component

Yukari Fujimoto 1 , Natsumi Hirata 1 , Emi Kashiwabara 1 , Junichiro Kishi 1 , Etsuko Nabika 1 , Yohei Arai 1 , Takanori Matsumaru 1 , Shinsuke Inuki 1,2

1 Keio University, Yokohama, Japan, 2 Kyoto University, Kyoto, Japan

CD1d is a non-polymorphic MHC class I-like molecule present on cells such as dendritic cells, and its ligands include glycolipids such as α-GalCer (KRN7000). Complexes of glycolipid ligands and CD1d are recognized by T cell receptors (TCR) on NKT cells and induce the secretion of various cytokines, including Th1 and Th2 cytokines. Although Th2-biasing CD1d ligands are attractive potential candidates for adjuvants and therapeutic drugs for autoimmune diseases, the number of potent ligands is limited, and their biasing mechanism remain unclear.

In the present research, we have identified a series of novel Th2-biasing CD1d glycolipid ligands based on modification of their lipid part of α-GalCer structure [1,2]. These have shown high binding affinities and efficient Th2 cytokine production, and even truncated acyl chain-containing variants still retain their binding affinities and agonistic activities, which can be associated with an “anchoring effect.” i.e. formation of a buried hydrogen bond between a polar group (eg. amide) on the acyl chain and the CD1d lipid-binding pocket. Our analysis also indicated that the appearance rates of ligand-CD1d complexes on the cell surface were involved in Th2-biasing responses. We demonstrated that the ligands, having the “anchor” in the shorter lipid part, would be one of the most potent Th2-biasing ligands with keeping the total cytokine induction levels, among the known ligands.

a) Inuki, S.; Aiba, T.; Hirata, N.; Ichihara, O.; Yoshidome, D.; Kita, S.; Maenaka, K.; Fukase, K.; Fujimoto, Y. ACS Chem. Biol. 2016, 11, 3132. b) Inuki, S.; Kashiwabara, E.; Hirata, N.; Kishi, J.; Nabika, E.; Fujimoto, Y. Angew. Chem. Int. Ed. 2018, 57, 9655.

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