Control of CD1d-restricted antigen presentation and inflammation by sphingomyelin

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 (AS...

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Published in:	Nature immunology Vol. 20; no. 12; pp. 1644 - 1655
Main Authors:	Melum, Espen, Jiang, Xiaojun, Baker, Kristi D., Macedo, M. Fatima, Fritsch, Jürgen, Dowds, C. Marie, Wang, Jing, Pharo, Anne, Kaser, Arthur, Tan, Corey, Pereira, Catia S., Kelly, Samuel L., Duan, Jingjing, Karlsen, Tom H., Exley, Mark A., Schütze, Stefan, Zajonc, Dirk M., Merrill, Alfred H., Schuchman, Edward H., Zeissig, Sebastian, Blumberg, Richard S.
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01-12-2019 Nature Publishing Group
Subjects:	631/250 692/420/256 Animal models Animals Antigen Presentation Antigens Antigens, CD1d - metabolism Biomedical and Life Sciences Biomedicine CD1d antigen Cell activation Cell Differentiation Clonal Selection, Antigen-Mediated Enzyme Replacement Therapy Enzymes Humans Immunology Infectious Diseases Inflammation Inflammation - immunology Lipid metabolism Lipids Lymphocyte Activation Lymphocyte Count Medical colleges Mice Mice, Inbred C57BL Mice, Knockout Natural killer cells Natural Killer T-Cells - immunology Niemann-Pick disease Niemann-Pick Diseases - genetics Phenotypes Phospholipids Sphingomyelin Sphingomyelin phosphodiesterase Sphingomyelin Phosphodiesterase - genetics Sphingomyelin Phosphodiesterase - metabolism Sphingomyelins - immunology Sphingomyelins - metabolism Thymus Gland - immunology Portugal Germany
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Summary:	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. Niemann–Pick disease is characterized by the cellular accumulation of sphingomyelin. Blumberg and colleagues use both mouse models and materials from patients with Niemann–Pick disease to show that sphingomyelin accumulation inhibits CD1d-restricted NKT cell activation and development.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 E.M. designed, performed and analyzed experiments with R.S.B. E.M., S.Z. and R.S.B. wrote the manuscript. X.J., K.D.B., C.M.D., A.P. and C.T. helped with experiments. M.F.M. and C.S.P. provided and analyzed human samples for NKT cells. S.Z. provided lentiviruses expressing CD1d and contributed to the design of experiments and the interpretation of results. J.F. and S.S. performed extraction of lysosomes. J.W. and D.M.Z. performed the IEF experiments and determined the CD1d-sphingomyelin structure. A.K., T.H.K. and M.A.E. provided scientific input. S.L.K., J.D. and A.H.M. performed mass spectometry and analyzed the lipidomics data together with E.M. E.H.S. provided Asm−/− mice and rhASM and assisted in the analysis of experiments. R.S.B. supervised the studies. Author contributions
ISSN:	1529-2908 1529-2916
DOI:	10.1038/s41590-019-0504-0