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Control of CD1d-restricted antigen presentation and inflammation by sphingomyelin.

Accepted version
Peer-reviewed

Type

Article

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Authors

Jiang, Xiaojun 
Baker, Kristi D 
Fritsch, Jürgen 

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.

Description

Keywords

Animals, Antigen Presentation, Antigens, CD1d, Cell Differentiation, Clonal Selection, Antigen-Mediated, Enzyme Replacement Therapy, Humans, Inflammation, Lymphocyte Activation, Lymphocyte Count, Mice, Mice, Inbred C57BL, Mice, Knockout, Natural Killer T-Cells, Niemann-Pick Diseases, Sphingomyelin Phosphodiesterase, Sphingomyelins, Thymus Gland

Journal Title

Nat Immunol

Conference Name

Journal ISSN

1529-2908
1529-2916

Volume Title

20

Publisher

Springer Science and Business Media LLC

Rights

All rights reserved