1. The Protein Crystallography Unit, ARC Centre of Excellence in Structural and Functional Microbial Genomics, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia
2. Department of Microbiology & Immunology, University of Melbourne, Parkville, Victoria 3010, Australia
3. School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK

Correspondence to: James McCluskey²Jamie Rossjohn¹ Correspondence and requests for materials should be addressed to J.R. (Email: jamie.rossjohn@med.monash.edu.au) or J.M. (Email: jamesm1@unimelb.edu.au).

Abstract

The CD1 family is a large cluster of non-polymorphic, major histocompatibility complex (MHC) class-I-like molecules that bind distinct lipid-based antigens that are recognized by T cells. The most studied group of T cells that interact with lipid antigens are natural killer T (NKT) cells, which characteristically express a semi-invariant T-cell receptor (NKT TCR) that specifically recognizes the CD1 family member, CD1d. NKT-cell-mediated recognition of the CD1d–antigen complex has been implicated in microbial immunity, tumour immunity, autoimmunity and allergy. Here we describe the structure of a human NKT TCR in complex with CD1d bound to the potent NKT-cell agonist -galactosylceramide, the archetypal CD1d-restricted glycolipid. In contrast to T-cell receptor–peptide-antigen–MHC complexes, the NKT TCR docked parallel to, and at the extreme end of the CD1d-binding cleft, which enables a lock-and-key type interaction with the lipid antigen. The structure provides a basis for the interaction between the highly conserved NKT TCR -chain and the CD1d–antigen complex that is typified in innate immunity, and also indicates how variability of the NKT TCR -chain can impact on recognition of other CD1d–antigen complexes. These findings provide direct insight into how a T-cell receptor recognizes a lipid-antigen-presenting molecule of the immune system.

1. The Protein Crystallography Unit, ARC Centre of Excellence in Structural and Functional Microbial Genomics, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia
2. Department of Microbiology & Immunology, University of Melbourne, Parkville, Victoria 3010, Australia
3. School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK

Correspondence to: James McCluskey²Jamie Rossjohn¹ Correspondence and requests for materials should be addressed to J.R. (Email: jamie.rossjohn@med.monash.edu.au) or J.M. (Email: jamesm1@unimelb.edu.au).

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