This information is informing the design of synthetic iNKT-cell antigens. The iNKT cells may be activated by exogenous antigen, or by a combination of dendritic cell-derived interleukin-12 and iNKT TCR–self-antigen–CD1d engagement. The iNKT-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 RG-7204 iNKT-cell activation. In a range of bacterial infections, dendritic cell-dependent innate activation of iNKT cells through interleukin-12 is the dominant influence on their activity. Invariant MG-132 nmr natural killer T (iNKT) cells recognize antigen (foreign or endogenous glycolipid) presented by the non-classical MHC class I-like molecule CD1d. In common with conventional T cells, they are selected in the thymus on the basis of their T-cell receptor (TCR) affinity for ligand. The term ‘invariant’ derives from the very restricted TCR used by these cells; the iNKT TCR comprises Vα24Jα18 in humans and Vα14Jα18 in mice, paired with Vβ11 in humans and Vβ2, Vβ7 or Vβ8.2 in mice. Phenotypically, iNKT cells are characterized by expression of NK markers and memory effector T-cell markers.[1] Other NKT-cell types exist (collectively termed ‘type 2’ NKT cells) but will not be

considered in this review. The CD1d structure, containing two deep hydrophobic pockets,[2]

suggested that it could present lipid antigen, and in 1997 the prototype iNKT-cell ligand α-galactosylceramide (αGalCer) was identified in marine sponge extract.[3] Fluorescently labelled tetramers of CD1d loaded with αGalCer have enabled the development and activation of iNKT cells to be characterized in great detail.[4] In response to antigen, iNKT cells mount a rapid response, releasing substantial amounts of cytokine within hours of activation. They are among the first lymphocytes to produce interferon-γ (IFN-γ) in response to bacterial infection,[5] and contain pre-formed cytokine mRNA to enable their reaction speed.[6] Fast release of cytokines by activated iNKT cells is sufficient to transactivate other lymphocytes Sulfite dehydrogenase and shape the course of a subsequent adaptive response. The iNKT-cell response to αGalCer includes secretion of the T helper type 1 (Th1) cytokine IFN-γ and Th2 cytokine interleukin-4 (IL-4).[7] However, other iNKT-cell antigens may elicit a response polarized towards Th2 or Th1 cytokine release. Synthetic Th1-biasing or Th2-biasing iNKT-cell ligands have been developed to exploit this for therapeutic effect.[8, 9] A range of pathogen-derived iNKT-cell antigens have been characterized,[10] and accumulation of self-antigen can also activate iNKT cells.