Memory CD8 T cells in aged female mice more often express genes from the usually inactive X chromosome
Memory CD8 T cells in aged female mice more often express genes from the usually inactive X chromosome
On August 28, bioRxiv published a preprint about memory CD8 T cells, the T lymphocytes that retain information about past infections. The authors found that these cells in aged female mice more often expressed genes from the usually inactive X chromosome.
Female mammals have two X chromosomes. During early development, each cell inactivates one of them so that most X-linked genes retain a single functional copy. Some genes are still expressed from the inactive chromosome. These are known as genes that escape X inactivation. A 2025 study had already found that such escape events become more frequent with age across mouse organs. It remained uncertain which cells produced this signal.
The authors of the new preprint crossed two mouse strains whose X chromosomes differ at many DNA variants. These variants allowed them to determine which X chromosome was active in each cell and whether its RNA came from the active copy or the usually inactive copy. They sequenced RNA and measured chromatin accessibility in 268 936 individual cells from the spleens of three-month-old and two-year-old animals. Chromatin is the packaged form of DNA, and its accessibility affects whether genes can be transcribed. In aged females, memory CD8 T cells had more than twice as many genes escaping X inactivation as any other immune cell type. Regions of the inactive X chromosome were also more often accessible for transcription.
The researchers then compared T-cell receptor sequences. Cells with the same sequence belong to the same clone, meaning that they descend from a single original T cell. Among memory CD8 T cells from aged females, the proportion of effector-like cells with high expression of the Ccl5 gene increased. These cells are more prepared to respond immediately to infection. They accounted for 21.9%, compared with 8.7% in aged males. In females, 72% of these cells belonged to especially large clones, and genes escaped X inactivation more often in the most expanded clones. The authors therefore traced a signal previously detected across an entire organ to a specific cell population and its history of division.
Using the OneK1K dataset, the authors studied 975 donors aged 19 to 97 years. This dataset does not allow expression to be assigned separately to the two X chromosomes in humans, so the researchers calculated an adjusted activity score for 93 known genes that escape X inactivation. In central memory CD8 T cells, a subtype of memory cells, this score increased with age in women. The authors found no such trend in men.
The association observed in mice is consistent with two possible sequences of events. Repeated encounters with infectious antigens and subsequent cell divisions may gradually weaken silencing of the second X chromosome. Alternatively, genes that begin to be expressed from the second X chromosome may give activated cells an advantage during clonal expansion. The next experiment will need to determine which event occurs first.