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Nat Immunol. 2019 Dec;20(12):1644-1655. doi: 10.1038/s41590-019-0504-0. Epub 2019 Oct 21.

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

Author information

1
Gastroenterology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. espen.melum@medisin.uio.no.
2
Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Rikshospitalet, and University of Oslo, Oslo, Norway. espen.melum@medisin.uio.no.
3
Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Rikshospitalet, and University of Oslo, Oslo, Norway.
4
Gastroenterology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
5
Department of Oncology, Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada.
6
i3S Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
7
Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.
8
Department of Medical Sciences, University of Aveiro, Aveiro, Portugal.
9
Institute of Immunology, Christian-Albrechts University, Kiel, Germany.
10
Department of Infection Prevention and Infectious Diseases, University of Regensburg, Regensburg, Germany.
11
Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Christian-Albrechts University, Kiel, Germany.
12
Division of Immune Regulation, La Jolla Institute for Immunology, La Jolla, CA, USA.
13
Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
14
School of Biological Sciences and the Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA, USA.
15
Human Aging Research Institute, School of Life Sciences, Nanchang University, Nanchang, China.
16
Department of Internal Medicine, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
17
Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
18
Department of Medicine I, University Medical Center Dresden, Technische Universität Dresden, Dresden, Germany.
19
Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany.
20
Gastroenterology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. rblumberg@bwh.harvard.edu.

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.

PMID:
31636468
DOI:
10.1038/s41590-019-0504-0

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