Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 49, Pages E4753-E4761Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1310050110
Keywords
autoreactivity; inflammation; innate immunity; lipid binding proteins
Categories
Funding
- Wellcome Trust [084923/B/08/Z, 084923Z/08/Z]
- Cancer Research UK [C399/A2291]
- Advanced Immunization Technologies Grant [280873]
- Medical Research Council
- MRC [G1000800, G1001750, MC_UU_12010/1] Funding Source: UKRI
- Cancer Research UK [11331] Funding Source: researchfish
- Medical Research Council [MC_UU_12010/1, G1001750, G1000800, G1000800e] Funding Source: researchfish
Ask authors/readers for more resources
Lipid transfer proteins, such as molecules of the saposin family, facilitate extraction of lipids from biological membranes for their loading onto CD1d molecules. Although it has been shown that prosaposin-deficient mice fail to positively select invariant natural killer T (iNKT) cells, it remains unclear whether saposins can facilitate loading of endogenous iNKT cell agonists in the periphery during inflammatory responses. In addition, it is unclear whether saposins, in addition to loading, also promote dissociation of lipids bound to CD1d molecules. To address these questions, we used a combination of cellular assays and demonstrated that saposins influence CD1d-restricted presentation to human iNKT cells not only of exogenous lipids but also of endogenous ligands, such as the self-glycosphingolipid beta-glucopyranosylceramide, up-regulated by antigen-presenting cells following bacterial infection. Furthermore, we demonstrated that in human myeloid cells CD1d-loading of endogenous lipids after bacterial infection, but not at steady state, requires trafficking of CD1d molecules through an endo-lysosomal compartment. Finally, using BIAcore assays we demonstrated that lipid-loaded saposin B increases the off-rate of lipids bound to CD1d molecules, providing important insights into the mechanisms by which it acts as a lipid editor, capable of fine-tuning loading and unloading of CD1d molecules. These results have important implications in understanding how to optimize lipid-loading onto antigen-presenting cells, to better harness iNKT cells central role at the interface between innate and adaptive immunity.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available