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.
Highlights
Genetic studies in yeast and other model organisms have implicated several pathways in the aging process
The formation of an immunological synapse between a T cell and an antigen-bearing APC is required for T cell activation, T cell receptor (TCR)-dependent signals are initiated within smaller structures distributed throughout the immunological synapse [26,27,28]
When we compared the subspecies composition of the young and old groups, we found that the overall decrease in total Glc-Cer in aged CD4+ T cells was primarily due to the loss of the shorter chain-length C16, C18, C20, and C22 subspecies (Fig. S1, p,0.05); much smaller differences were observed with the longer chain-length C24:1, C24, C26:1, and C26 subtypes
Summary
Genetic studies in yeast and other model organisms have implicated several pathways in the aging process. Genes involved in the control of metabolism, stress resistance, chromatindependent gene regulation and genome stability are frequently selected in mutational studies of longevity regulation [1,2]. Products of sphingolipid metabolism, such as ceramides (Cer), modulate many of these pathways [3]. In turn, modulate signaling pathways that operate in response to these stressful insults. These pathways control basic cellular processes, such as cell cycle progression, which is usually interrupted to allow certain cellular repair mechanisms to operate, or apoptosis, which may be triggered if the stressful insult overwhelms the cell’s capacity for auto-repair [7,8]
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