New ways to turn on NKT cells

Abstract

Natural killer T (NKT) cells are CD1d-restricted, lipid antigen-reactive T cells with powerful immunoregulatory potential. The prototypic antigen for NKT cells is a marine sponge-derived glycolipid, α-galactosylceramide (α-GalCer), but this is not normally encountered in the mammalian environment. Thus, there is great interest in the identification of more physiological stimuli for NKT cells, and numerous studies have shown that NKT cells are capable of responding to a range of microbial lipid-based antigens. Two new studies expand our understanding of environmental NKT cell stimuli, with one showing that CD1d-restricted NKT cell antigens are present within common house dust extract (HDE), whereas the other shows that NKT cells can respond to innate stimuli irrespective of the presence of foreign microbial antigens. Collectively, these two investigations indicate that NKT cells are far more likely to encounter foreign antigens, or innate activating signals, than previously recognized, suggesting a more central role for these cells in the immune system.

Figure 1.

Two pathways of NKT cell activation in response to common environmental stimuli. (A) HDE is essentially ubiquitous, and most samples were found to contain CD1d-restricted Ags (orange hexagons) that are recognized by NKT TCRs (Wingender et al., 2011) and TLR ligands (brown circles; Batzer et al., 2007). Both components are important for the adjuvant effects of HDE (Batzer et al., 2007; Wingender et al., 2011). (B) Some, but not all, bacteria carry CD1d-restricted lipid Ags that are recognized by NKT TCRs, yet NKT cells respond to most bacterial infections. Irrespective of whether a particular strain carries these Ags, the NKT cell response is dominated by innate, TLR, and MyD88-dependent signaling that results in IL-12 (green squares)–mediated stimulation of NKT cells, rather than by bacterial glycolipid Ag recognition (Brigl et al., 2011). The response is also at least partly CD1d dependent, again, irrespective of the presence of bacterial CD1d-restricted lipid Ags, suggesting the recognition of self-lipid Ags in conjunction with the IL-12–mediated stimulation (Brigl et al., 2011). Thus, there are at least two pathways for NKT cell activation: (1) TCR mediated and (2) cytokine mediated. NKT TCR-mediated recognition of foreign lipid-based Ags presented by CD1d that appears to be important for the adjuvant effects of HDE (A), but less so for the response to bacterial infection, whereas innate, inflammatory cytokine–mediated stimulation of NKT cells appears to dominate the response to bacterial infection (B). In the context of bacterial infections, NKT cells may concurrently recognize self- (blue hexagons) or bacterial (orange hexagons) glycolipids, but regardless, the innate (IL-12– and TLR-mediated) stimuli appear to be critical for NKT cell activation.