Antigen specificity of invariant natural killer T-cells

Abstract

Natural killer T-cells, with an invariant T-cell antigen receptor α-chain (iNKT cells), are unique and conserved subset of lymphocytes capable of altering the immune system through their rapid and potent cytokine responses. They are reactive to lipid antigens presented by the CD1d molecule, an antigen-presenting molecule that is not highly polymorphic. iNKT cell responses frequently involve mixtures of cytokines that work against each other, and therefore attempts are underway to develop synthetic antigens that elicit only strong interferon-gamma (IFNγ) or only strong interleukin-4 responses but not both. Strong IFNγ responses may correlate with tighter binding to CD1d and prolonged stimulation of iNKT cells, and this may be useful for vaccine adjuvants and for stimulating anti-tumor responses. iNKT cells are self-reactive although the structure of the endogenous antigen is controversial. By contrast, bacterial and fungal lipids that engage the T-cell receptor and activate IFNγ from iNKT cells have been identified from both pathogenic and commensal organisms and the responses are in some cases highly protective from pathogens in mice. It is possible that the expanding knowledge of iNKT cell antigens and iNKT cell activation will provide the basis for therapies for patients suffering from infectious and immune diseases and cancer.

Keywords: Glycolipid; Immune system; Natural killer T-cells.

Fig. 1

CD1d lipid binding pocket showing A′ and F′ grooves with α-galactosylceramide bound to CD1d for reference.

Fig. 2

Some representative Th1 and Th2 cytokine skewing lipids compared to α-galactosylceramide.

Fig. 3

Two T-helper Type 1 skewing lipids crystallized in complex with mouse CD1d and the invariant Natural Killer T-cell receptor. PDB files: napthylurea, α-galactosylceramide (PDB code: 3QUZ), SMC (PDB code: 3TVM).

Fig. 4

Proposed endogenous ligands for invariant natural killer T-cells. Top: Crystal structures of tri-molecular complexes and the corresponding glycosphingolipid antigen structures are indicated. Bottom: Phospholipid-containing putative self-antigens.

Fig. 5

Induced fit by the invariant natural killer T-cell receptor with iGb3 showing the carbohydrate head group before and after T-cell receptor engagement. In A, only the sugar linked to the ceramide lipid could be resolved, presumably because the position of the two distal sugars was not fixed in the crystal. iGB3 before engagement (PDB code: 2Q7Y) and after engagement (PDB code: 3RZC) shown in comparison to α-galactosylceramide (PDB code: 3HE6).

Fig. 6

Invariant natural killer T-cell microbial lipids that have been crystallized in complex with mouse CD1d and the mouse invariant natural killer T-cell receptor.

Fig. 7

Invariant natural killer T-cell microbial lipids that currently have not been crystallized in complex with CD1d and the mouse invariant natural killer T-cell receptor.