Strategy of lipid recognition by invariant natural killer T cells: 'one for all and all for one'

Abstract

Invariant natural killer T (iNKT) cells are evolutionarily conserved lipid-reactive T cells that bridge innate and adaptive immune responses. Despite a relatively restricted T-cell receptor (TCR) diversity, these cells respond to a variety of structurally distinct foreign (i.e. microbial or synthetic) as well as host-derived (self-) lipid antigens presented by the CD1d molecule. These multi-tasking lymphocytes are among the first responders in immunity, and produce an impressive array of cytokines and chemokines that can tailor the ensuing immune response. Accordingly, iNKT cells play important functions in autoimmune diseases, cancer, infection and inflammation. These properties make iNKT cells appealing targets in immune-based therapies. Yet, much has to be learned on the mechanisms that allow iNKT cells to produce polarized responses. Responses of iNKT cells are influenced by the direct signals perceived by the cells through their TCRs, as well as by indirect co-stimulatory (and potentially co-inhibitory) cues that they receive from antigen-presenting cells or the local milieu. A decade ago, biochemists and immunologists have started to describe synthetic lipid agonists with cytokine skewing potential, paving a new research avenue in the iNKT cell field. Yet how iNKT cells translate various antigenic signals into distinct functional responses has remained obscure. Recent findings have revealed a unique and innate mode of lipid recognition by iNKT cells, and suggest that both the lipid antigen presented and the diversity of the TCR modulate the strength of CD1d-iNKT TCR interactions. In this review, we focus on novel discoveries on lipid recognition by iNKT cells, and how these findings may help us to design effective strategies to steer iNKT cell responses for immune intervention.

Figure 1

T-cell receptor-β (TCR-β) chain, TCR affinity and modulation of invariant natural killer T (iNKT) cell responses. TCR-β chain amino acid composition has been shown to modulate the affinity/avidity of CD1d–lipid recognition (depicted is αGalCer). As TCR affinity increases (from the right, lighter green shade, to the left, darker green shade), individual iNKT cell clones gain the ability to recognize and respond to lower potency lipid antigens, such as iGb3, potentially other glycosphingolipids (GSLs) and phospholipids, while retaining the ability to respond to high-potency lipids such as αGalCer or OCH9. Whether the strength of TCR signalling influences the magnitude (upward-pointing arrows) and/or quality (depicted as differing IFN-γ/IL-4 ratios) of cytokines secreted by individual clones, and how this affects the overall iNKT cell response, remain open questions. Note that the ordering of the lipids depicted here constitutes a tentative summary of their relative potencies, measured by different methods, such as immunization, antigen presentation assay, tetramer staining or affinity measurements, based on the available data.

Figure 2

Potential consequences of the ‘one-size-fits-all’ docking topology. Invariant natural killer (iNKT) T-cell receptors (TCRs) recognize CD1d presenting structurally distinct lipids in a conserved manner. Within this conserved docking framework, fine interactions between the antigen and the TCR-α chain can differ (depicted as pink dots), but their functional consequences remain unclear. Although distinct lipids trigger iNKT cell responses of differing magnitudes (αGalCer is a strong agonist, iGb3 a weaker antigen), consensus information linking iNKT cell polarization and antigenic stimulus is lacking. iNKT TCRs have been shown to reshape the CD1d–lipid landscape to reach the conserved interaction mode. As such, the glycan head group of iGb3 (depicted) is pushed away and squashed flat over CD1d. It is possible that for glycosphingolipids (GSLs) (or other glycolipids) with more protruding head groups, this conformational gymnastics is impossible and the TCR cannot reach CD1d (far right, depicted is GT1b). The presentation of such compounds by CD1d molecules may constitute a way to regulate iNKT cell activation.