Submitted to: PLoS One
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/13/2012
Publication Date: 10/26/2012
Citation: Molano, A., Huang, Z., Marko, M.G., Azzi, A., Wu, D., Wang, E., Kelly, S.L., Merrill, A.H., Bunnell, S.C., Meydani, S.N. 2012. Age-dependent changes in the sphingolipid composition of CD4+ T cell membranes and immune synapses implicate glucosylceramides in age-related T cell dysfunction. PLoS One. doi:10.1371/journal.pone.0047650. Interpretive Summary: The immune response declines as we grow older, leading to a higher chance of getting sick or dying from infectious diseases like the flu or pneumonia. This decline also reduces the chances that vaccines will work against these diseases. Given that the aging are a growing segment of population world-wide, it is important to understand why this decline happens so that we can find out if there is some way of reversing it. In this study, we focused on a specific immune cell that plays a critical role in ensuring an effective immune response: the helper CD4+ T cell, because as humans grow older, these cells multiply less and less, which results in a poor defense against microbes. In an animal study, we investigated one biochemical change that may influence the weakened response of CD4+ T cells as they get older. This change involves a variety of compounds called sphingolipids, which are important in cell communication and recognition. We found increased amounts of all but one group of these compounds in aged CD4+ T cells. Importantly, after we added a compound to increase these decreased compounds in the aged CD4+ T cells, we were able to partially improve their immune response. While these experiments were only done in a test tube, they suggest a way of making old CD4+T cells work better. The next step would be to test the compound in aging animals. If no side effects occur, we might find a future strategy to improve the immune response of elderly humans, particularly after vaccinations, so that we might strengthen their resistance to serious and often fatal diseases.
Technical Abstract: Sphingolipid (SL4) composition can influence the biophysical properties of cell membranes. Additionally, specific SL modulate signaling pathways involved in proliferation, senescence, and apoptosis. We investigated age-dependent changes in the SL composition of CD4+ T cells, and the impact of these changes on T cell function. For these studies, immune synapse (IS5) and non-IS fractions were prepared from the CD4+ T cells of young and old mice by magnetic immuno-isolation and were subjected to sphingolipidomic analysis. Both the non-IS and IS fractions of aged CD4+ T cells contained higher molar amounts of sphingomyelins, dihydrosphingomyelins and ceramides. In contrast, the non-IS fractions of aged CD4+T cells contained significantly lower molar amounts of glucosylceramides. After normalization for total sphingolipid content, a statistically significant decrease in the abundance of glucosylceramides was evident in the non-IS and IS fractions of aged T cells. This change was predominantly balanced by increases in the molar fractions of sphingomyelins and dihydrosphingomyelins in aged CD4+ T cells. In vitro enhancement of ceramide levels decreased CD4+ T cell proliferation without regard for the age of the responding T cells. In contrast, in vitro enhancement of glucosylceramide levels preferentially increased the proliferation of aged CD4+ T cells. These results suggest that shifts in SL metabolism contribute to age-related impairments in CD4+ T cell function.