Age-Dependent Changes in the Sphingolipid Composition of Mouse CD4(+) T Cell Membranes and Immune Synapses Implicate Glucosylceramides in Age-Related T Cell Dysfunction

作者：Molano Alberto; Huang Zhaofeng; Marko Melissa G; Azzi Angelo; Wu Dayong; Wang Elaine; Kelly Samuel L; Merrill Alfred H Jr; Bunnell Stephen C^*; Meydani Simin Nikbin

来源：PLos One, 2012, 7(10): e47650.

DOI：10.1371/journal.pone.0047650

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.

• 出版日期2012-10-26