In a recent publication in the journal Nature Immunology, Espen Melum at the Norwegian PSC research center and a large international team of collaborators provide evidence that a natural occurring lipid can dramatically affect the function of NKT-cells.
Espen Melum summarizes the findings:
Natural Killer T (NKT) cells are characterized by the expression of cellular markers for natural killer (NK) and T-cells, but compared to classical T-cells that react to peptide antigens presented by MHC molecules, NKT cells are reactive to lipid antigens presented by CD1 molecules. Since NKT cells are present at a high frequency in the liver we believe that they represent important regulator in various liver diseases.
We hypothesized that endogenous lipids might play an important regulatory role by damping activation of NKT cells. In order to investigate this, we used material from humans with the disease Niemann-Pick disease that have a deficiency in the enzyme acid sphingomyelinase (ASM) and the mouse model for this disease (Asm-/- mice). Both humans with Niemann-Pick diseases and the mouse models have an overload of the lipid sphingomyelin. We found that overload of spingomyelin severely affects the development and activation of NKT cells and that different NKT driven diseases models were affected. The molecular underpinnings of this effect were determined using lipidomics and structural modelling. Finally, we demonstrated that this defect was amenable to therapy in mice, either by bone-marrow transplantation or enzyme replacement.
Control of CD1d-restricted antigen presentation and inflammation by sphingomyelin.
Melum E, Jiang X, Baker KD, Macedo MF, Fritsch J, Dowds CM, Wang J, Pharo A, Kaser A, Tan C, Pereira CS, Kelly SL, Duan J, Karlsen TH, Exley MA, Schütze S, Zajonc DM, Merrill AH, Schuchman EH, Zeissig S, Blumberg RS.
Nat Immunol. 2019 Dec;20(12):1644-1655. doi: 10.1038/s41590-019-0504-0. Epub 2019 Oct 21.
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