The GM2 ganglioside inhibits iNKT cell responses in a CD1d-dependent manner
| Autor: | N. Alegrete, Elisa Leão-Teles, Ana Maria Minarelli Gaspar, Macedo Mf, M.T. Cardoso, Begoña Pérez-Cabezas, Helena Ribeiro, Catia S. Pereira |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Endocrinology Diabetes and Metabolism Cell Galactosylceramides Lymphocyte Activation Biochemistry Peripheral blood mononuclear cell Glycosphingolipids 03 medical and health sciences Mice 0302 clinical medicine Endocrinology Antigen Gangliosidoses GM2 Genetics medicine Animals Humans Molecular Biology Ganglioside biology Chemistry Lipid metabolism Cell biology carbohydrates (lipids) 030104 developmental biology medicine.anatomical_structure CD1D biology.protein Natural Killer T-Cells lipids (amino acids peptides and proteins) Antibody Antigens CD1d Cell activation 030215 immunology |
| Zdroj: | Molecular genetics and metabolism. 125(1-2) |
| ISSN: | 1096-7206 |
| Popis: | Invariant natural killer T (iNKT) cells are a subset of T lymphocytes that recognize lipid antigens presented on CD1d molecules at the surface of antigen-presenting cells. GM2 is a glycosphingolipid abundant in cellular membranes and known to bind CD1d molecules, but the functional consequences of this binding are not completely clarified. Herein, we analyzed the effect of GM2 in iNKT cell activation. We found that culturing antigen-presenting cells or total peripheral blood mononuclear cells with GM2 did not induce activation of human iNKT cells, implying that this lipid is not antigenic for human iNKT cells. To investigate if this lipid could inhibit iNKT cell activation, we simultaneously incubated antigen-presenting cells with GM2 and the iNKT cell antigen α-Galactosylceramide (α-GalCer) and used them to stimulate iNKT cells. We found that GM2 reduced human iNKT cell activation in a dose-dependent manner. An explanation for this effect could be a direct competition of GM2 with antigenic lipids for CD1d binding. This was demonstrated by the use of an antibody (L363) that stains mouse CD1d:α-GalCer complexes, as in the presence of GM2 the amount of CD1d:α-GalCer complexes are reduced. We further explored the consequences of chronic GM2 overload on human iNKT cells by analyzing iNKT cells in patients diagnosed with GM2 gangliosidoses. We found that pediatric patients present a higher frequency of circulating CD4+ iNKT cells and concomitant lower frequency of CD4−CD8− iNKTs. A lower percentage of iNKT cells expressing the NK marker CD161 was also observed in these patients. In contrast, in two adult patients studied, no differences on iNKT cell phenotype were observed. Altogether, this study uncovers a new role for GM2 in the modulation of iNKT cell activation, thus strengthening the central role of lipid metabolism in iNKT cell biology. |
| Databáze: | OpenAIRE |
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