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Age-Related Dip in Immune Cell Coordination Detected in Single-Cell Mouse Study

NEW YORK (GenomeWeb) – A new single-cell analysis has uncovered an age-related rise in the transcriptional variability of stimulated mouse immune cells, providing a potential explanation for declining immune effectiveness in elderly animals.

A UK research team, led by investigators at the University of Cambridge, the Wellcome Trust Sanger Institute, and the European Molecular Biology Laboratory's European Bioinformatics Institute, compared transcriptional patterns in individual effector memory CD4+ T cells from young or old mice that had or had not been exposed to immune stimulants.

While the stimulated immune cells appeared to marshal a conserved transcriptional response in the young animals, the aging mouse T cells were marked by heterogeneity and diminished activation an apparent "core activation program," the researchers reported in Science yesterday.

"Imagine the immune system as a 'cell army,' ready to protect the body from infection. Our research revealed that this army is well coordinated in young animals, with all the cells working together like a Greek phalanx to block infection," co-corresponding author Duncan Odom, a researcher affiliated with the University of Cambridge and the Wellcome Trust Sanger Institute, said in a statement.

In contrast, the variability detected by single-cell transcriptome sequencing on T cells from the older animals seemed to represent declining immune cell coordination suspected of dulling the immune system's responsiveness, he explained.

"Although individual cells might still be strong, the lack of coordination between them makes their collective effectiveness lower," Odom said.

As part of a broader effort to understand the expression changes that accompany aging, the researchers focused on naïve and memory CD4+ T cells, using single-cell RNA-seq to profile individual T cells isolated from Mus musculus domesticus and M. musculus castaneus mouse spleen tissue with Fluidigm's C1 system.

As anticipated from past studies, they saw that the transcriptional patterns identified in individual T cells isolated from younger, three-month-old mice from both sub-species were tightly regulated after immune stimulation with plate-bound antibodies.

In particular, the team detected more than 2,000 genes with altered expression after immune stimulation, along with a corresponding dip in overall gene expression variability from one cell to the next in the young animals. But in the older mice, which were 21 months old, on average, the extent of the characteristic immune response and the coordination of between-cell expression profiles in the T cells appeared to wane.

"The discovery that CD4+ T cells from aged mice are less able to robustly up-regulate a core activation program may in part explain the aging-associated decrease of immune function observed across mammals," the authors concluded. "Our results indicate that in addition to transcriptional dysregulation and chromatin destabilization, increased cell-to-cell transcriptional variability is a major hallmark of aging."