Scavenger receptors target glycolipids for natural killer T cell activation
Stefan Freigang, … , Albert Bendelac, Luc Teyton
Stefan Freigang, … , Albert Bendelac, Luc Teyton
Published October 15, 2012
Citation Information: J Clin Invest. 2012;122(11):3943-3954. https://doi.org/10.1172/JCI62267.
View: Text | PDF
Research Article Article has an altmetric score of 12

Scavenger receptors target glycolipids for natural killer T cell activation

Abstract

NKT cells are innate-like T cells with powerful regulatory functions that are a promising target for immunotherapy. The efficacy of glycolipids, such as the prototypic NKT cell antagonist α-galactosylceramide (αGalCer), is currently being evaluated in clinical trials, but little is known about factors that target lipid antigens for CD1d 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 CD1d presentation of other important NKT cell agonists remains unclear. We therefore investigated receptor-mediated uptake pathways for CD1d presentation using a panel of structurally diverse lipid antigens. We found that uptake via scavenger receptors was essential for the CD1d 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 characteristics 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 CD1d presentation and identify structural motifs that may prove useful for therapeutic NKT cell vaccination.

Authors

Stefan Freigang, Elise Landais, Victoria Zadorozhny, Lisa Kain, Kenji Yoshida, Yang Liu, Shenglou Deng, Wulf Palinski, Paul B. Savage, Albert Bendelac, Luc Teyton

×

Figure 3

The requirement for SRA or LDLR for CD1d presentation of NKT cell agonists is determined by the chemical structure of the lipid antigen head group.

Options: View larger image (or click on image) Download as PowerPoint
The requirement for SRA or LDLR for CD1d presentation of NKT cell agonis...
(A) CD1d presentation of a panel of NKT cell agonists (chemical structures are depicted in Figure 2) to DN32.D3 NKT hybridoma cells by Ldlr–/– DCs (black circles, top panels) and by Sra–/– DCs (black circles, bottom panels) as compared with the respective WT DCs (white circles, both panels). (B) The dose-response curves for the data shown in Figure 1 and part A were used to calculate the ΔEC50 in order to compare the requirements of individual lipid antigens for uptake via the LDLR or the SRA pathway. (C) CD1d presentation of indicated NKT cell agonists by WT, Cd1d–/–, Sra–/–, and Ldlr–/– DCs to primary WT NKT cells in vitro. Data represent the mean ± SEM of triplicate determinations from 1 of 3 (A and B) or 2 (C) independent experiments.