Scavenger receptors target glycolipids for natural killer T cell activation
Stefan Freigang, Elise Landais, Victoria Zadorozhny, Lisa Kain, Kenji Yoshida, Yang Liu, Shenglou Deng, Wulf Palinski, Paul B. Savage, Albert Bendelac, Luc Teyton
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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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 8

Differential contribution of individual uptake pathways to NKT cell responses in vivo.

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Differential contribution of individual uptake pathways to NKT cell resp...
(A–E) In vivo NKT cell responses of immunized WT (white bars), Sra–/– (black bars), and Ldlr–/– (gray bars) mice in response to i.v. injection of indicated lipid antigens as assessed (A) by CD1d tetramer staining of blood lymphocytes on day 3 after infection and (B) serum IFN-γ and (C) serum IL-4 responses determined at 11 and 3 hours after immunization, respectively. (D and E) NKT cell help for the priming of OVA-specific CD8+ T cell responses in mice immunized with OVA and indicated NKT cell agonists. OVA-specific CD8+ responses were evaluated on day 8 after immunization by (D) staining of lymphocytes with OVA-specific MHC class I tetramers and (E) intracellular cytokine staining after restimulation with specific peptide. Circles depict individual mice, and bars represent the mean ± SEM for groups of 5–6 mice. *P < 0.05; **P < 0.01.