Memory T cells responsible for long-term immunity have been cross-trained

Like employees cross-trained for different jobs, scientists have the strongest evidence yet that memory T cells responsible for long-term immune protection also served another role. The finding provides insight that should help researchers design more effective vaccines and expand cancer immunotherapies.

The complementary studies of research in mice and humans appear online today in the scientific journal Nature. Investigators 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. Understanding their origins should aid efforts to harness the immune cells to prevent or cure diseases.

"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. He is first and corresponding author of one study and co-author of related research in humans that appears in the same issue. The co-corresponding author of both papers is Rafi Ahmed, Ph.D., an Emory professor in the Department of Microbiology and 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 rapidly respond if the virus or other threat re-appears.

Prior to these studies, other researchers suggested that effector and memory T cells develop as distinct lineages from naïve T cells. Naïve T cells are less differentiated, 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, 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 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. DNA methylation helps regulate gene expression. Tagging DNA with a methyl group can repress gene expression. Removing the methyl group, a process known as 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, 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. Researchers 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.

Youngblood and his colleagues are using the findings to explore how to generate precision immunotherapies primed to recognize and attack patients' tumors. The findings also suggest possible strategies to enhance vaccine effectiveness.

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The other authors are J. Scott Hale, Haydn Kissick, Eunseon Ahn, Xiaojin Xu, Andreas Wieland, Koichi Araki, Erin West, Carl Davis, Bogumila Konieczny, Rustom Antia and Xiaodong Cheng, all of Emory; and Hazem Ghoneim, Yiping Fan and Pranay Dogra, all of St. Jude. The research was funded in part by grants (AI17891, AI030048, AI057266, AI114442) from the National Institutes of Health; and ALSAC, the fundraising and awareness organization of St. Jude.

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