| Literature DB >> 31636468 |
Espen Melum1,2, Xiaojun Jiang3, Kristi D Baker4,5, M Fatima Macedo6,7,8, Jürgen Fritsch9,10, C Marie Dowds11, Jing Wang12, Anne Pharo3, Arthur Kaser13, Corey Tan4,3, Catia S Pereira6,7, Samuel L Kelly14, Jingjing Duan14,15, Tom H Karlsen3, Mark A Exley4, Stefan Schütze9, Dirk M Zajonc12,16, Alfred H Merrill14, Edward H Schuchman17, Sebastian Zeissig11,18,19, Richard S Blumberg20.
Abstract
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 in the thymus, 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-deficient mice. Together, these results demonstrate that control of non-agonistic CD1d-associated lipids is critical for iNKT cell development and function in vivo and represents a tight link between cellular sphingolipid metabolism and immunity.Entities:
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Year: 2019 PMID： 31636468 PMCID： PMC7249499 DOI： 10.1038/s41590-019-0504-0
Source DB: PubMed Journal: Nat Immunol ISSN： 1529-2908 Impact factor: 25.606