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  • Review Article
  • Published:

Recognition of CD1d-restricted antigens by natural killer T cells

Key Points

  • The principles that underlie the interaction of the type I natural killer T (NKT) cell T cell receptor (TCR) with CD1d are distinct from those that govern the interaction of the TCR of conventional T cells with their peptide–MHC ligands.

  • Type I NKT TCRs consistently adopt a parallel docking mode over the F′-pocket of CD1d that is independent of TCR chain usage or of the antigen that is presented on the CD1d molecule. This indicates that the NKT TCR acts in a manner akin to a pattern-recognition receptor.

  • Within the consensus type I NKT TCR–antigen–CD1d footprint, variations in TCR α- and β-chain usage can determine the levels of CD1d-mediated autoreactivity and the degree of antigen specificity.

  • The type I NKT cell TCR can 'bulldoze' distinct ligands, including β-linked self glycolipid ligands, such that they mimic the conformation of the α-linked antigens, thereby enabling the consensus type I NKT TCR–antigen–CD1d footprint.

  • The affinity of the type I NKT TCR–antigen–CD1d interaction is a good measure of the efficacy of an antigen at stimulating NKT cells, whereas the T helper 1 (TH1)- and TH2-biasing properties of an antigen seem to be more attributable to CD1d loading considerations and the features of the antigen itself.

  • The type II NKT TCR has been shown to dock above the A′-pocket of CD1d. Thus, type II NKT TCRs can interact with antigen–CD1d complexes in a markedly different manner from type I NKT TCRs.

Abstract

Natural killer T (NKT) cells are innate-like T cells that rapidly produce a variety of cytokines following T cell receptor (TCR) activation and can shape the immune response in many different settings. There are two main NKT cell subsets: type I NKT cells are typically characterized by the expression of a semi-invariant TCR, whereas the TCRs expressed by type II NKT cells are more diverse. This Review focuses on the defining features and emerging generalities regarding how NKT cells specifically recognize self, microbial and synthetic lipid-based antigens that are presented by CD1d. Such information is vitally important to better understand, and fully harness, the therapeutic potential of NKT cells.

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Figure 1: NKT cells.
Figure 2: CD1d-mediated antigen presentation.
Figure 3: Structural comparison between NKT TCR–lipid–CD1d complexes and the conventional TCR–peptide–MHC complex.
Figure 4: The footprint of contact made by NKT TCRs on the surface of CD1d.
Figure 5: Changes in the conformation of the lipid or CD1d following binding to NKT TCRs.
Figure 6: Modes of NKT cell activation.

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Acknowledgements

This work was supported by the US National Institutes of Health (grants AI090450 and AI092108), Australian National Health and Medical Research Council (NHMRC) program and project grants, Cancer Council Victoria and the Australian Research Council (ARC). D.I.G. was supported by an NHMRC Senior Principal Research Fellowship; J.R. was supported by an NHMRC Australia Fellowship. O.P. was supported by an ARC Future Fellowship.

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Glossary

γδ T cells

T cells express either a T cell receptor (TCR) composed of α- and β-subunits (αβTCR) or a TCR composed of γ- and δ-subunits (γδTCR). The majority (more than 90%) of human T cells express αβ TCRs, which mainly recognize antigenic peptides bound to conventional MHC class I or II molecules. T cells that express γδTCRs are less abundant, and the ligands for these receptors are less well characterized.

Altered peptide ligands

(APLs). Peptides that are analogues of an original antigenic peptide. They commonly have amino acid substitutions at residues that make contact with the T cell receptor (TCR). TCR engagement by these APLs usually leads to partial or incomplete T cell activation. Some APLs (antagonists) can specifically antagonize and inhibit T cell activation by the wild-type antigenic peptide.

Peroxisome

An indispensable cytoplasmic organelle that has essential roles in antioxidant defence, cholesterol and bile-acid synthesis, eicosanoid metabolism and the β- and ω-oxidation of long-chain and very-long-chain fatty acids.

Mucosa-associated invariant T cells

(MAIT cells). A population of innate-like lymphocytes. MAIT cells express an evolutionarily conserved invariant T cell receptor and are selected by the MHC class I-related molecule MR1. They are abundant in human blood, in the intestinal mucosa and in mesenteric lymph nodes, and they can produce interferon-γ in response to various bacterial infections.

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Rossjohn, J., Pellicci, D., Patel, O. et al. Recognition of CD1d-restricted antigens by natural killer T cells. Nat Rev Immunol 12, 845–857 (2012). https://doi.org/10.1038/nri3328

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