Scientists report that they have shown conclusively that memory T cells responsible for long-term immune protection arise from effector CD8 T cells. The finding provides insight that should help researchers design more effective vaccines and expand cancer immunotherapies by aiding efforts to harness the immune cells to prevent or cure diseases.
The study (“Effector CD8 T Cells Dedifferentiate into Long-Lived Memory Cells”) appears in Nature. Researchers at St. Jude Children's Research Hospital and the Emory University School of Medicine led the research, which addressed a long-running debate about the origin of memory CD8 T cells. These white blood cells are essential for long-term immune protection.
“Memory CD8 T cells that circulate in the blood and are present in lymphoid organs are an essential component of long-lived T cell immunity. These memory CD8 T cells remain poised to rapidly elaborate effector functions upon re-exposure to pathogens, but also have many properties in common with naive cells, including pluripotency and the ability to migrate to the lymph nodes and spleen. Thus, memory cells embody features of both naive and effector cells, fuelling a long-standing debate centred on whether memory T cells develop from effector cells or directly from naive cells,” write the investigators. “Here we show that long-lived memory CD8 T cells are derived from a subset of effector T cells through a process of dedifferentiation.”
“This research provides the most compelling evidence yet that memory CD8 T cells arise from effector CD8 T cells and, in fact, must transit through an effector stage of differentiation before becoming memory cells,” said Ben Youngblood, Ph.D., an assistant member of the St. Jude Department of Immunology.
Effector CD8 T cells combat viral infections, cancer, and other threats. In contrast, memory CD8 T cells function like sentries and circulate throughout the body, ready to recognize and respond rapidly if the virus or other threat reappears.
Prior to these studies, other researchers suggested that effector and memory T cells develop as distinct lineages from naïve and less differentiated T cells, which means they can fashion themselves to respond to novel viruses and other threats encountered by the immune system.
Working in mice with a viral infection, Dr. Youngblood and his colleagues showed how memory CD8 T cells arise from a small subset of effector CD8 T cells. Those results supported similar findings about human memory CD8 T cells in research led by Emory scientists.
The analysis by Dr. Youngblood and his colleagues included epigenetic and gene expression data as well as analysis of next-generation whole-genome bisulfide sequencing, which captures DNA methylation. Tagging DNA with a methyl group can repress gene expression. Demethylation allows the gene to be switched on.
The investigators reported that the memory CD8 T cells retained epigenetic traces of their time as effector cells combating active infections.
Using gene expression, gene knockout, and other methods, the researchers showed effector cells that become memory CD8 T cells undergo demethylation. That allows the cells destined to become memory CD8 T cells to express genes associated with naïve T cells and transition from effector to memory T cells. The scientists showed the cells retained that capability even when transferred to another mouse.
The demethylation, combined with the effector T cell methylation patterns that memory T cells retain, also left the memory CD8 T cells poised to recognize and rapidly respond to previously seen viruses or other threats.
Dr. Youngblood and his colleagues are using the findings to explore how to generate precision immunotherapies primed to recognize and attack patients' tumors. The research also suggests possible strategies to enhance vaccine effectiveness.