Lipid and Carbohydrate Modifications of α-Galactosylceramide Differently Influence Mouse and Human Type I Natural Killer T Cell Activation

Abstract

Background:Several synthetic glycosphingolipids have been tested to determine their capacity to activate type I NKT cells. Results: Although the TCR binds with high affinity to all CD1d-presented glycolipids, only a few activate type I NKT cells in vivo. Conclusion: TCR binding affinity does not necessarily predict antigenicity in vivo.Significance: The prediction of the therapeutic efficacy of type I NKT cell antigens requires complementary assays.

Natural Vaccine Adjuvants and Immunopotentiators Derived From Plants, Fungi, Marine Organisms, and Insects

“…50 The immunomodulatory Th1 or Th2 effect of a-GalCer molecules can be varied by chemical modification of their sugar and fatty acyl chains, as well as by shortening the lipid chain Natural Adjuvants and Immunopotentiators length. 51 Vaccine formulations containing natural GalCer or synthetic derivatives with different antigens have been found to be protective against viral infections and tumors in animal models. 52,53 Tengvall et al 54 demonstrated that intranasal immunization of a herpes virus type 2 glycoprotein (gD) with a-GalCer conferred complete protection against lethal vaginal herpes simplex virus-2 challenge in mice.…”

Donor-unrestricted T cells in the human CD1 system

“…For example, the same kind of antigen can take a clockwise or counterclockwise orientation within the toroidal A′ pocket of CD1d (Wu et al 2006; Li et al 2010; Birkholz et al 2015). Lipid ligands show flexible lipid positioning and association of multiple lipids within one CD1 molecule, especially for CD1b, which has an unusually large cavity with four interconnected pockets that has been described as a “maze for alkyl chains” (Gadola et al 2002) (Fig.…”

Synthesis of C-5″ and C-6″-modified α-GalCer analogues as iNKT-cell agonists

“…The crystal structure of the ternary mCD1d- 5b -TCR complex indicates that the binding mode of 5b in the parallels that of NU-α-GalCer. In particular, its naphthylcarbamate moiety also induces a hydrophobic pocket in CD1d by displacement of Met69 (Figure 4), 23 indicating that the naphthyl moiety drives the observed induced fit rather than the nature of the linker, given that the length of the latter is appropriate. Probably, this extra interaction with CD1d compensates for the observed loss of the hydrogen bond between the 4″-OH group and Asn-30 of the TCR.…”