Turned on by danger: activation of CD 1d‐restricted invariant natural killer T cells

Summary CD 1d‐restricted invariant natural killer T ( iNKT ) cells bear characteristics of innate and adaptive lymphocytes, which allow them to bridge the two halves of the immune response and play roles in many disease settings. Recent work has characterized precisely how their activation is initiated and regulated. Novel antigens from important pathogens have been identified, as has an abundant self‐antigen, β‐glucopyranosylcaramide, capable of mediating an i NKT ‐cell response. Studies of the i NKT T‐cell receptor ( TCR )–antigen– CD 1d complex show how docking between CD 1d–antigen and i NKT TCR is highly conserved, and how small sequence differences in the TCR establish intrinsic variation in i NKT TCR affinity. The sequence of the TCR CDR 3β loop determines i NKT TCR affinity for ligand– CD 1d, independent of ligand identity. CD 1d ligands can promote T helper type 1 ( T h1) or T h2 biased cytokine responses, depending on the composition of their lipid tails. Ligands loaded into CD 1d on the cell surface promote T h2 responses, whereas ligands with long hydrophobic tails are loaded endosomally and promote T h1 responses. This information is informing the design of synthetic i NKT ‐cell antigens. The i NKT cells may be activated by exogenous antigen, or by a combination of dendritic cell‐derived interleukin‐12 and i NKT TCR –self‐antigen– CD 1d engagement. The i NKT ‐cell activation is further modulated by recent foreign or self‐antigen encounter. Activation of dendritic cells through pattern recognition receptors alters their antigen presentation and cytokine production, strongly influencing i NKT ‐cell activation. In a range of bacterial infections, dendritic cell‐dependent innate activation of i NKT cells through interleukin‐12 is the dominant influence on their activity.