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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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 7

The class A SR SRA controls the bioactivity of αGalCer in vivo.

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The class A SR SRA controls the bioactivity of αGalCer in vivo. (A–D) Se...
(A–D) Serum cytokine responses upon αGalCer injection in the indicated receptor-deficient (black circles) and WT control mice (white circles). CD1d-deficient mice served as negative controls (white triangles). (E and F) Expansion of NKT cells of receptor-deficient (black circles) and WT control mice (white circles) in response to i.v. injection of αGalCer as assessed by CD1d tetramer staining of blood lymphocytes. (G and H) NKT cell help for the priming of OVA-specific CD4+ and CD8+ T cell responses in αGalCer/OVA-immunized Ldlr–/– mice but not in Sra–/– mice. Receptor-deficient mice (black bars) and their respective WT control mice (white bars) were immunized with OVA and αGalCer, and OVA-specific CD8+ and CD4+ T cell responses were evaluated on day 8 after immunization by staining of splenocytes with OVA-specific MHC class I and II tetramers. Irrelevant influenza hemagglutinin-specific tetramers served as negative control. Data of 3 (A–F) and 2 (G and H) independent experiments using groups of 4 mice are shown as mean ± SEM. *P < 0.05.