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.
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Research Article

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

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Figure 6

Functional NKT cell responses in Ldlr–/– and Sra–/– mice.

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Functional NKT cell responses in Ldlr–/– and Sra–/– mice. (A–C) NKT ce...
(A–C) NKT cell populations in thymus, spleen, and liver of naive Sra–/–, Ldlr–/–, and WT mice were identified by (A) CD1d/αGalCer-tetramer staining and further characterized by the surface expression of (B) CD4 and (C) NK1.1. (D) CD1d expression on thymocytes and splenocytes of Sra–/–, Ldlr–/–, and WT mice. FACS plots of a single, representative mouse per strain are shown. Bar graphs depict the mean ± SEM for groups of 4–6 mice from 1 of 3 independent experiments. (E) CD1d presentation of endogenous lipid antigens to NKT cell hybridoma cells by thymocytes of indicated strains. (F–H) The response of Ldlr–/–, Sra–/–, and WT NKT cells to stimulation with in vitro αGalCer-pulsed WT DCs was assessed (F) in vitro by their IFN-γ production or in vivo by (G) their serum cytokine responses and (H) proliferation in blood. *P < 0.05; **P < 0.01. Data are shown as mean ± SEM from 1 experiment with groups of 4 mice that has been repeated twice with similar results.