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Glycolipid immunology: How to hide in a surveillance society

Surface maps of two NKT cell TCRs. Click here for more information.

The outer membrane of gram-negative bacteria contains glycolipids that strongly activate immune cells, notably lipopolysaccharide (LPS), which can cause septic shock. Apart from LPS, glycosphingolipds (GSLs) which have the fatty amino alcohol sphingosine attached to a glycan activate natural killer T (NKT) cells when presented by CD1d. As the chain of the NKT cell T cell receptor (TCR) does not vary, it is as yet unclear how NKT cells recognize structurally variable GSLs. Two studies now elucidate the molecular basis for this recognition, and show how bacteria can hide from NKT cell surveillance.

Reporting in Nature Immunology, Scott-Browne et al. created a T cell hybridoma cell line that expressed a TCR containing the invariant V-J regions of the mouse TCR chain which is also conserved in human NKT cell TCRs. The authors exposed the cells to monosaccharidic GSLs that had very different fatty acid chains and monosaccharidic head groups. Surprisingly, cells expressing a single TCR could were able to recognize and respond to six different glycolipid antigens. Thus, human NKT cells carrying TCRs composed of identical regions are able to recognize different microbial GSLs.

Expanding on a recent structural study of the GSL-TCR complex, the authors discovered that the recognition region of the TCR was composed entirely of germline-encoded amino acid residues from the CDR3, CDR1 and CDR2 chains, and that the remaining TCR chains did not significantly contribute to antigen binding. Furthermore, site-directed mutagenesis revealed that in each case the same amino acid residues were involved in glycolipid binding. The surface of TCR-bound GSL antigens was significantly smaller than that of peptide antigens; however, the binding constants were equal to or higher than the peptide antigens. Interestingly, the germline-coded recognition of microbial GSLs strongly resembles the recognition of other microbial compounds, such as LPS, by Toll-like receptors.

Reporting in Nature Chemical Biology, Long et al. synthesized three glycolipids from the Sphingomonas bacterial species that are known to cause nosocomical infections. Surprisingly, only monosaccharide GSLs elicited a strong immune response, while GSLs possessing tri- or tetrasaccharides led to a weak response. This finding supports the hypothesis that the lysosomes of antigen presenting cells do not contain glucosidases that are able to process GSL di- and triglycosylmoieties, resulting in the presence of monosaccharidic GSLs which boost the immune response. Furthermore, these results indicate that the synthesis of oligosaccharides by bacterial species such as Sphingomonas might be a mechanism of immune evasion.

Both studies greatly enhance our understanding of glycolipid immunology. The study of Scott-Browne et al. clarifies how diverse microbial GSLs can be recognized by invariant NKT-TCRs, while the results of Long et al. shed light on a possible strategy by which bacteria alter the carbohydrate component of GSLs to escape from the NKT recognition.

Author: Mirko von Elstermann