title: Age-dependent changes in the sphingolipid composition of mouse CD4+ T cell membranes and immune synapses implicate glucosylceramides in age-related T cell dysfunction.
abstract: To determine whether changes in sphingolipid composition are associated with age-related immune dysfunction, we analyzed the core sphingolipidome (i.e., all of the metabolites through the first headgroup additions) of young and aged CD4(+) T cells. Since sphingolipids influence the biophysical properties of membranes, we evaluated the compositions of immune synapse (IS) and non-IS fractions prepared by magnetic immuno-isolation. Broadly, increased amounts of sphingomyelins, dihydrosphingomyelins and ceramides were found in aged CD4(+) T cells. After normalizing for total sphingolipid content, a statistically significant decrease in the molar fraction of glucosylceramides was evident in both the non-IS and IS fractions of aged T cells. This change was balanced by less dramatic increases in the molar fractions of sphingomyelins and dihydrosphingomyelins in aged CD4(+) T cells. In vitro, the direct or enzymatic enhancement of ceramide levels decreased CD4(+) T cell proliferation without regard for the age of the responding T cells. In contrast, the in vitro inhibition of glucosylceramidase preferentially increased the proliferation of aged CD4(+) T cells. These results suggest that reductions in glucosylceramide abundance contribute to age-related impairments in CD4(+) T cell function.
authors.affiliation: Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts, United States of America.
authors.forename: Alberto
authors.initials: A
authors.lastname: Molano
authors.forename: Zhaofeng
authors.initials: Z
authors.lastname: Huang
authors.forename: Melissa G
authors.initials: MG
authors.lastname: Marko
authors.forename: Angelo
authors.initials: A
authors.lastname: Azzi
authors.forename: Dayong
authors.initials: D
authors.lastname: Wu
authors.forename: Elaine
authors.initials: E
authors.lastname: Wang
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Kelly
authors.forename: Alfred H
authors.initials: AH
authors.lastname: Merrill
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Bunnell
authors.forename: Simin Nikbin
authors.initials: SN
authors.lastname: Meydani
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D002462:Cell Membrane / Q000378:metabolism*; D002470:Cell Survival; D002518:Ceramides / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013107:Sphingolipids / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism*
chemical_list: D002518:Ceramides; D013107:Sphingolipids