Scavenger receptors target glycolipids for natural killer T cell activation.

NKT cells are innate-like T cells with powerful regulatory functions that are a promising target for immuno-therapy. The efficacy of glycolipids, such as the prototypic NKT cell antagonist cx-galactosylceramide (αGalCer), is currently being evaluated in clinical trials, but little is known about factors that target lipid antigens for CD Id presentation and NKT cell activation in vivo. Lipid uptake via the LDL receptor (LDLR) has been shown for digalactosylceramide; however, whether this pathway contributes to CDld presentation of other important NKT cell agonists remains unclear. We therefore investigated receptor-mediated uptake pathways for CDld presentation using a panel of structurally diverse lipid antigens. We found that uptake via scavenger recep-tors was essential for the CDld presentation of αGalCer and Sphingomonas glycolipids. Moreover, in vivo NKT cell responses, i.e., cytokine production, proliferation, and NKT cell help for adaptive CD4+ and CD8+ T cells, required the uptake of αGalCer via scavenger receptor A. Importantly, our data indicate that structural char-acteristics of glycolipids determine their receptor binding and direct individual lipids toward different uptake pathways. These results reveal an important contribution of scavenger receptors in the selection of lipids for CDld presentation and identify structural motifs that may prove useful for therapeutic NKT cell vaccination. [ABSTRACT FROM AUTHOR]