Lysosomal storage disorders prevent the proper action of some natural killer T (NKT) cells, according to Gadola et al. (page 2293).

NKT cells recognize glycosphingolipid (GSL) antigens presented on the surface of various cell types. Recognition of endogenous GSL antigens leads to the positive selection of NKT cells in the thymus. Once in the periphery, NKT cells can induce an immune response if presented with GSLs of foreign origin.

The overaccumulation of GSLs in lysosomes is a common feature of lysosomal storage disorders. Here, Gadola and colleagues show that this congestion impairs the intracellular processing and presentation of GSLs in the antigen-presenting cells of mouse models of lysosomal storage disorders.

The authors reasoned that, given their reliance on GSLs for selection, NKT cells might be impaired in the disease model mice. They found that, although the mice had normal NKT cells in terms of development and function, the numbers of these cells were dramatically reduced compared with wild-type mice. The simplest explanation for the low numbers, says coauthor Frances Platt, is that the impaired presentation of endogenous GSLs in the thymus leads to fewer NKT cells making it through the positive selection stage.

The mouse models differ in the particular lysosomal component affected, but they all accumulate GSL in their lysosomes. It will thus be interesting to determine whether the broad spectrum of human GSL storage disorders also lack NKT cells and whether this defect could help explain in part the clinical heterogeneity of these disorders.