Abstract
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.
Highlights
Plasma membrane cholesterol plays a critical role in cell signaling by stabilizing protein receptors within close proximity to liquid-ordered phase microdomains called lipid rafts [1]
The kinetics of membrane cholesterol accumulation in resting CD4 T-cells from F1 mice given a single dose of squalene (180 mg/mouse) indicated that the peak cholesterol load occurs after 7 days, with a gradual decrease within the following two weeks till reaching physiological levels
Cholesterol-rich microdomains known as lipid rafts are postulated to be a driving force in immunological synapse formation and critical for T-cell signaling [1,59,60,61]
Summary
Plasma membrane cholesterol plays a critical role in cell signaling by stabilizing protein receptors within close proximity to liquid-ordered phase microdomains called lipid rafts [1]. Ligand-mediated clustering of neighboring receptor subunits into rafts leads to the assembly of fully functional receptors able to signal for T cell development, maturation, activation, and differentiation [7,8,9,10]. These processes occur upon formation of T cell-APC immunological synapse and TCR- peptide-MHC complex interactions [11,12]. Clustering of rafts leading to T cellAPC immunological synapse formation may occur in a non antigen-specific manner upon cross-linking of GM1 gangliosides by bacterial proteins such as cholera toxin B-subunit [13,14,15] or cross-linking of carbohydrate moieties of various protein receptors by galectins [16,17]
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