PloS one, 2012-06, Vol.7 (6), p.e38733
2012
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- Autor(en) / Beteiligte
- Titel
- Increased membrane cholesterol in lymphocytes diverts T-cells toward an inflammatory response
- Ist Teil von
- PloS one, 2012-06, Vol.7 (6), p.e38733
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2012
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Cell signaling for T-cell growth, differentiation, and apoptosis is initiated in the cholesterol-rich microdomains of the plasma membrane known as lipid rafts. Herein, we investigated whether enrichment of membrane cholesterol in lipid rafts affects antigen-specific CD4 T-helper cell functions. Enrichment of membrane cholesterol by 40-50% following squalene administration in mice was paralleled by an increased number of resting CD4 T helper cells in periphery. We also observed sensitization of the Th1 differentiation machinery through co-localization of IL-2Rα, IL-4Rα, and IL-12Rβ2 subunits with GM1 positive lipid rafts, and increased STAT-4 and STAT-5 phosphorylation following membrane cholesterol enrichment. Antigen stimulation or CD3/CD28 polyclonal stimulation of membrane cholesterol-enriched, resting CD4 T-cells followed a path of Th1 differentiation, which was more vigorous in the presence of increased IL-12 secretion by APCs enriched in membrane cholesterol. Enrichment of membrane cholesterol in antigen-specific, autoimmune Th1 cells fostered their organ-specific reactivity, as confirmed in an autoimmune mouse model for diabetes. However, membrane cholesterol enrichment in CD4(+)Foxp3(+) T-reg cells did not alter their suppressogenic function. These findings revealed a differential regulatory effect of membrane cholesterol on the function of CD4 T-cell subsets. This first suggests that membrane cholesterol could be a new therapeutic target to modulate the immune functions, and second that increased membrane cholesterol in various physiopathological conditions may bias the immune system toward an inflammatory Th1 type response.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0038733Titel-ID: cdi_plos_journals_1326188395
- Format
- –
- Schlagworte
- Animals, Antigen-presenting cells, Antigens, Antilipemic agents, Apoptosis, Autoimmunity - drug effects, Biology, Canda, CD28 antigen, CD3 antigen, CD4 antigen, CD4-Positive T-Lymphocytes - immunology, CD4-Positive T-Lymphocytes - metabolism, Cell differentiation, Cell Differentiation - immunology, Cholesterol, Cholesterol - metabolism, Counseling services, Cytokines, Dendritic cells, Diabetes mellitus, Differentiation (biology), Enrichment, Female, Foxp3 protein, Gangliosides, Gene Expression Regulation - drug effects, Growth factors, Health sciences, Helper cells, Immune system, Immunology, Inflammation, Inflammation - genetics, Inflammation - immunology, Inflammation - metabolism, Inflammatory response, Influenza, Interleukin 12, Interleukin 2 receptors, Ligands, Lipid rafts, Lipids, Localization, Lymphocytes, Lymphocytes T, Machinery and equipment, Male, Medicine, Membrane Microdomains - drug effects, Membrane Microdomains - metabolism, Mice, Mice, Transgenic, Phosphorylation, Protein Transport, Proteins, Psoriasis, Rafts, Receptors, Cytokine - genetics, Receptors, Cytokine - metabolism, Rodents, Signal Transduction, Signaling, Squalene, Squalene - administration & dosage, Squalene - pharmacology, Stat5 protein, Stimulation, T cell receptors, T cells, T-Lymphocyte Subsets - cytology, T-Lymphocyte Subsets - drug effects, T-Lymphocyte Subsets - immunology, T-Lymphocyte Subsets - metabolism, T-Lymphocytes, Regulatory - immunology, T-Lymphocytes, Regulatory - metabolism, Th1 Cells - immunology, Th1 Cells - metabolism, Tropical diseases