NKT cells sense bacterial infection and recognize bacterial glycolipids

We reported that the invariant TCR expressed by mouse and human NKT cells recognizes glycosphingolipids with α branched sugars, which are unique to Sphingomonas bacteria. This provides a direct mechanism for microbial recognition by NKT cells, as opposed to the indirect mechanism described above. The NKT cell response to Sphingomonas is driven by TCR recognition rather than APC-derived cytokines, and mice that lack NKT cells have reduced bacterial clearance, especially in the liver. Sphingomonas are not highly pathogenic, however, and it remained unknown if NKT cells can recognize other classes of glycolipids derived from pathogenic microbes. We show that mouse and human NKT cells with an invariant TCR recognize glycosyl diacylglycerols from Borrelia burgdorferi, which causes Lyme disease. Interestingly, the response to these compounds was highly dependent on the nature of the aliphatic chains, with the addition of a single unsaturated bond having an enormous influence on antigenic potency. The responses of mouse and human NKT cells differ, because the human CD1d groove preferentially presents lipids that have more unsaturated bonds. NKT cells are activated during B. burgdorferi infection, and the glycolipid from B. burgdorferi stimulated NKT cell cytokine release. This response required TCR recognition and was independent of MyD88 activation of APC. These data provide evidence that NKT cells recognize a new category of microbial glycolipids, diacylglycerols, which is more broadly distributed in pathogenic microbes, and they suggest that this TCR-mediated recognition provides protection from microbial pathogens. Supported by US NIH grants AI45053, AI 69296, and AI71922.