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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.

plos one

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