Lysosomal Glycosphingolipid Recognition by NKT Cells

TLDR

NKT cells are a distinct T cell lineage expressing a conserved αβ TCR and NK receptors, yet their endogenous lipid ligands remain unidentified. The study proposes that peripheral expression of the lysosomal glycosphingolipid iGb3 regulates NKT cell responses to infection, malignancy, and autoimmunity. We demonstrate that iGb3 is recognized by mouse and human NKT cells, and that mice deficient in β‑hexosaminidase b, which lack iGb3, exhibit severe NKT cell deficiency, indicating iGb3 drives NKT development.

Abstract

NKT cells represent a distinct lineage of T cells that coexpress a conserved alphabeta T cell receptor (TCR) and natural killer (NK) receptors. Although the TCR of NKT cells is characteristically autoreactive to CD1d, a lipid-presenting molecule, endogenous ligands for these cells have not been identified. We show that a lysosomal glycosphingolipid of previously unknown function, isoglobotrihexosylceramide (iGb3), is recognized both by mouse and human NKT cells. Impaired generation of lysosomal iGb3 in mice lacking beta-hexosaminidase b results in severe NKT cell deficiency, suggesting that this lipid also mediates development of NKT cells in the mouse. We suggest that expression of iGb3 in peripheral tissues may be involved in controlling NKT cell responses to infections and malignancy and in autoimmunity.