title: Effects of methyl-beta-cyclodextrin on T lymphocytes lipid rafts with aging.
abstract: Aging is associated with a decline in immune functions. Among them, T-cell activation is altered at several points of the signaling cascade following TCR engagement. Recent findings suggest that lipid rafts act as a platform in the initiation of T-cell activation. We have previously demonstrated that cholesterol content in T-cells increased with aging, especially in lipid rafts. Cholesterol, which is a major component of lipid rafts, serves to stabilize their structure. We hypothesized that restoring T-cell cholesterol content and membrane fluidity would restore, at least in part, T-cell function via lipid rafts. We measured the lipid rafts coalescence, the p56(Lck) and linker of activated T-cell (LAT) signaling molecules recruitment and activation, the cholesterol content and fluidity in T-cell membrane after different methyl-beta-cyclodextrin (MBCD) treatments. Our results show that high concentration of MBCD (10 mM) completely disorganized the lipid rafts in T-cell membranes of young and elderly donors, however, T-cells from elderly donors were less sensitive than T-cells of young donors to low concentration of MBCD (0.5 mM). p56(Lck) and LAT recruitment and activation were affected in T-cells of both aged groups. MBCD treatment did not affect the cholesterol content and fluidity of T-cell membranes of young donors, while the cholesterol content was decreased and fluidity increased in lipid rafts of elderly donors. These results suggested that cholesterol extraction by MBCD increased the fluidity and disrupted lipid rafts organization. The increase in cholesterol content in lipid rafts with aging and its decrease by biochemical extraction were able to affect early signaling molecules activation. Restoring cholesterol content and fluidity may have beneficial effects, however, MBCD disorganized the membrane and this might not completely restore the T-cell activation via lipid rafts with aging. Altogether these results suggest that defects in cholesterol cellular homeostasis may be part of T-cell immunosenescence via lipid rafts dysfunction.
authors.affiliation: Research Center on Aging, Sherbrooke Geriatric University Institute, University of Sherbrooke, Sherbrooke, Que., Canada J1H 5N4.
authors.forename: Anis
authors.initials: A
authors.lastname: Larbi
authors.forename: Nadine
authors.initials: N
authors.lastname: Douziech
authors.forename: Abdelouahed
authors.initials: A
authors.lastname: Khalil
authors.forename: Gilles
authors.initials: G
authors.lastname: Dupuis
authors.forename: Saber
authors.initials: S
authors.lastname: Gheraïri
authors.forename: Karl-Philippe
authors.initials: KP
authors.lastname: Guérard
authors.forename: Tamàs
authors.initials: T
authors.lastname: Fülöp
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000375:Aging / Q000276:immunology*; D002352:Carrier Proteins / Q000097:blood; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D003505:Cyclodextrins / Q000494:pharmacology*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000097:blood; D008560:Membrane Fluidity / Q000187:drug effects; D021962:Membrane Microdomains / Q000187:drug effects* / Q000378:metabolism; D008565:Membrane Proteins / Q000097:blood; D018613:Microscopy, Confocal; D010750:Phosphoproteins / Q000097:blood; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D047392:beta-Cyclodextrins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D003505:Cyclodextrins; C110810:LAT protein, human; D008565:Membrane Proteins; D010750:Phosphoproteins; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; D002784:Cholesterol; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)