Control of CD1d-restricted antigen presentation and inflammation by sphingomyelin.
Baker, Kristi D
Pereira, Catia S
Kelly, Samuel L
Karlsen, Tom H
Exley, Mark A
Zajonc, Dirk M
Schuchman, Edward H
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Melum, E., Jiang, X., Baker, K. D., Macedo, M. F., Fritsch, J., Dowds, C. M., Wang, J., et al. (2019). Control of CD1d-restricted antigen presentation and inflammation by sphingomyelin.. Nature immunology, 20 (12), 1644-1655. https://doi.org/10.1038/s41590-019-0504-0
Invariant natural killer T (iNKT) cells recognize activating self and microbial lipids presented by CD1d. CD1d can also bind non-activating lipids, such as sphingomyelin. We hypothesized that these serve as endogenous regulators and investigated humans and mice deficient in acid sphingomyelinase (ASM), an enzyme that degrades sphingomyelin. We show that ASM absence in mice leads to diminished CD1d-restricted antigen presentation and iNKT cell selection resulting in decreased iNKT cell levels and resistance to iNKT cell-mediated inflammatory conditions. Defective antigen presentation and decreased iNKT cells are also observed in ASM-deficient humans with Niemann-Pick Disease and ASM activity in healthy humans correlates with iNKT cell phenotype. Pharmacological ASM administration facilitates antigen presentation and restores the levels of iNKT cells in Asm–/– mice. Together, these results demonstrate that control of non-agonistic CD1d-associated lipids is critical for iNKT cell development and function in vivo and represent a tight link between cellular sphingolipid metabolism and immunity.
Thymus Gland, Animals, Mice, Inbred C57BL, Mice, Knockout, Humans, Mice, Niemann-Pick Diseases, Inflammation, Sphingomyelin Phosphodiesterase, Sphingomyelins, Lymphocyte Count, Lymphocyte Activation, Cell Differentiation, Antigen Presentation, Antigens, CD1d, Natural Killer T-Cells, Enzyme Replacement Therapy, Clonal Selection, Antigen-Mediated
External DOI: https://doi.org/10.1038/s41590-019-0504-0
This record's URL: https://www.repository.cam.ac.uk/handle/1810/297038
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