Abstract
Author SummaryInvariant natural killer T (iNKT) cells are an evolutionarily conserved population of immune cells that recognize lipid antigens. A protein called a T cell receptor for antigen (TCR) on the surface of these iNKT cells recognizes lipids bound to a protein called CD1d on the surface of antigen-presenting cells. Here we describe the three-dimensional structure of the complex that forms between CD1d and the iNKT TCR together with a glycolipid antigen from the infectious bacterium Streptococcus pneumoniae, which is a common cause of bacterial meningitis in adults and is responsible for many other pneumococcal infections. We determined the three-dimensional structure of the complex by X-ray crystallography. The data obtained allow us to understand the structural requirements that make this glycolipid a potent antigen for iNKT cells, and why the TCR of these cells recognizes a particular combination of hexose sugar and diacylglycerol lipid. Moreover, by mutating CD1d and using biophysical methods to study the mutant protein complexes, we analyzed the role of the protein–protein interface between CD1d and the TCR and found that it plays an important role in the stability, but not the formation, of the trimolecular complex containing glycolipid antigen.
Highlights
Invariant NKT cells are an evolutionarily conserved population of T lymphocytes able to respond to lipid antigens when presented by CD1d, a non-classical MHC class I–like molecule [1].Antigen recognition by Invariant natural killer T (iNKT) cells is mediated by a semiinvariant ab T cell receptor (TCR) formed by a conserved Va14Ja18 rearrangement (Va24-Va18 in humans), and a limited panel of pairing b chains (Vb8.2, Vb7, Vb2 in mouse; Vb11 in humans)
A protein called a T cell receptor for antigen (TCR) on the surface of these iNKT cells recognizes lipids bound to a protein called CD1d on the surface of antigenpresenting cells
We describe the three-dimensional structure of the complex that forms between CD1d and the iNKT TCR together with a glycolipid antigen from the infectious bacterium Streptococcus pneumoniae, which is a common cause of bacterial meningitis in adults and is responsible for many other pneumococcal infections
Summary
Invariant NKT cells (iNKT) are an evolutionarily conserved population of T lymphocytes able to respond to lipid antigens when presented by CD1d, a non-classical MHC class I–like molecule [1].Antigen recognition by iNKT cells is mediated by a semiinvariant ab T cell receptor (TCR) formed by a conserved Va14Ja18 rearrangement (Va24-Va18 in humans), and a limited panel of pairing b chains (Vb8.2, Vb7, Vb2 in mouse; Vb11 in humans). Invariant NKT cells (iNKT) are an evolutionarily conserved population of T lymphocytes able to respond to lipid antigens when presented by CD1d, a non-classical MHC class I–like molecule [1]. Glycosphingolipids from Sphingomonas spp. and diacylglycerol (DAG) ligands from Borrelia burgdorferi, the causative agent of Lyme disease, were identified to stimulate iNKT cells in a CD1d/ TCR-dependent manner [3,4,5,6,7]. As Sphingomonas spp. and B. burgdorferi are not responsible for widespread or lethal diseases, we considered it possible that more pathogenic organisms express iNKT antigens, which would account for the highly conserved nature of the CD1d-iNKT TCR interaction. Recent studies identified the structures of DAG compounds from the highly pathogenic Streptococcus pneumoniae (S. pneumoniae) and Group B streptococcus (GBS), which were able to stimulate iNKT cells [8]. The most potent S. pneumoniae antigen, Glc-DAG-s2, is characterized by having a sn-
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