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News & Blogs » Antibody Drug Development News » Memory T Cells: Function, Creation, and Origins | GenScript
An Introduction to Therapeutic Chimeric Antigen Receptor T Cells

Therapeutic Antibody Discovery Services

Memory T cells: how are they formed?

Dec. 20, 2017

T lymphocytes play a central role in protecting human beings against intracellular pathogens or tumor antigens that requires T-cell mediated immune responses. T cells, in particular CD8+ T cells, can be activated to kill cancer cells or infected cells after recognizing antigens. CD8+ T cells are composed of 3 major subsets including naïve, effector and memory T cells. Naïve T cells are the primary T cells that haven’t encountered pathogen before. Effector T cells are developed from naïve T cells when exposed to antigens. Most effector cells will be removed through apoptosis after pathogen elimination to maintain immune balance.

However, a small portion of long-lived T cells still remains for rapid response upon pathogen re-exposure. This kind of cells is called memory T cells. Because memory T cells have been trained to recognize specific antigens, they will trigger a faster and stronger immune response after encountering the same antigen. This is how vaccines work to protect us against infection.

memory t cell formation

Vaccines have been used for centuries. However, it’s still unclear that how memory T cells are generated despite of the fact that it is an understudied field. Understanding the origins of memory T cells will be beneficial to vaccine design. Two major models have been proposed to explain the mechanism behind. Model A supports the hypothesis that memory T cells are derived from naïve T cells; Model B suggests that a subset of effector cells gives rise to memory T cells.

Finally, this long lasting debate has an answer now. Two research teams, in common with one leader Dr. Rafi Ahmed at Emory University School of Medicine, published two papers online in Nature this week with the strong evidences agreeing with model B.

Both of the two papers focus on CD8+ T cells processing pathway. Akondy et al. utilized deuterium labeled human T cells after yellow fever virus vaccination to track CD8+ T cells [1], while Youngblood et al. employed mouse model to investigate the formation of memory T cells [2]. They checked the epigenetic modifications of naïve, effector and memory T cells, as well as DNA configuration in those three types of T cells.

DNA methylation, one kind of epigenetic alteration that is associated with gene repression, was analyzed by Youngblood and his colleagues. They found that DNA methylation determines function and status among three types of T cells. Both effector T cells and memory T cells have similar DNA methylation profiles for effector-function genes with less methyl group addition compared to naïve T cells, which favors rapid response to pathogen re-exposure for memory T cells. This strong evidence is consistent with model B. In addition, memory T cells need less methylation of naïve-associated genes to maintain long living stage after arising from effector T cells. The authors further identified a DNA methyltransferase called Dnmt3a which regulates T cells stages through DNA methylation.

Akondy et al. also analyzed the patterns of DNA accessibility and found that memory T cells present a chromatin accessibility pattern comparable to that of effector T cells. This provides further evidence supporting the idea that memory T cells are arisen from effector cells.

Both studies clearly demonstrated that memory T cells are generated from effector T cells through epigenetic modifications, and the studies also revealed that Dnmt3a works as a key DNA methyltransferase affecting the memory T cells formation. This new finding sheds light on better vaccine design strategy. In addition, it contributes to the improvement for immunotherapies targeting Dnmt3a.

Reference

[1].'Rama S. Akondy, et al.' Origin and differentiation of human memory CD8 T cells after vaccination. Nature. doi: 10.1038/nature24633.

[2].'Ben Youngblood, et al.' Effector CD8 T cells dedifferentiate into long-lived memory cells. Nature. doi: 10.1038/nature25144.

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