Functional and Structural Studies of a Novel Class of Type I Natural Killer T Cell Stimulators: the Aminocyclitol α-Galactosylceramide Analogues — ASN Events
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Functional and Structural Studies of a Novel Class of Type I Natural Killer T Cell Stimulators: the Aminocyclitol α-Galactosylceramide Analogues (#160)

Tang Yongqing 1 , Amadeu Llebaria 2 , Rhys Pryce 3 , Onisha Patel 4 , Jérôme Le Nours 1 , Ronal Rai 1 , Victoria Hughes 1 , Hui-Fern Koay 5 6 , Adam Uldrich 5 6 , Dale Godfrey 5 6 , Jamie Rossjohn 1
  1. Centre of Excellence, Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
  2. Department de Química Biomèdica, Institute de Química Avançada de Catalunya, Barcelona, Spain
  3. Cellular Structural Biology, University of Oxford, Oxford, UK
  4. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  5. The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
  6. Department of Microbiology and Immunology, University of Melbourne, Melbourne, VIC, Australia

Type I Natural Killer T (iNKT) cell activation requires the presentation of lipid-based antigens, such as the prototypical glycolipid α-Galactoceramide (α-GalCer), by the CD1d molecule to the NKT T-cell receptor (TCR). Upon activation, iNKT cells rapidly secret a vast range of cytokines, which can potentially promote immunity to a variety of tumours. However, the anti-tumour efficacy of αGalCer was found to be limited since it stimulated both pro-inflammatory (Th1) and anti-inflammatory (Th2) immune responses in an unpredictable manner in human trials. In the past decade, many modified analogues of α-GalCer were synthesized in order to better control the NKT cell responses, however, more potent α-GalCer analogues are yet to be developed. In that context, we investigated the functional and structural basis of a novel class of α-GalCer analogues, the aminocyclitol ligands (ACLs). We discovered that ACLs could stimulate both splenic iNKT cell expansion and Th1-type cytokine secretion, ranging from a strong level, comparable to those stimulated by α-GalCer, to a negligible level. Affinity measurements (Surface Plasmon Resonance) also indicated that ACLs yielding a stronger immune response presented also a higher affinity for the 2C12 NKT TCR. Despite the differences in the cell responses and binding affinities, the crystal structure of the 2C12 TCR in complex with mouse CD1d loaded with 6 distinct ACLs revealed that molecular interactions at the TCR-CD1d-ACL interface were similar to those with α-GalCer. Our results indicate that ACLs are a promising basis for α-GalCer analogue in the development of novel immunotherapeutics.