How Are Memory T Cells Created?

T lymphocytes play a central role in protecting human beings against intracellular pathogens or tumor antigens that require 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 pathogens before. Effector T cells develop 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.

From "The origins of memory T cells" Omilusik and Goldrath, 2017

Two proposed models for memory T cell formation: a. Memory T cells arise from naïve T cells or b. from effector T cells. Findings by Akondy et al. 2017 and Youngblood et al. 2017, where gene methylation patterns in naïve, effector and memory T cells were analyzed, supported that memory T cells derive from effector T cells.

Origin of memory T cells

Scientists have resolved the origin of memory T cells by studying DNA methylation in naïve, effector, and memory T cells.

Vaccines have been used for centuries. However, it’s still unclear how memory T cells are generated. Understanding the origins of memory T cells will be beneficial to vaccine design. Two major models have been proposed to explain their development. 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. Two research teams, in common with one leader Dr. Rafi Ahmed at Emory University School of Medicine, published two papers online in Nature with strong evidences supporting model B.

Both papers focus on the CD8+ T cell 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 a 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 by 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 lived memory after arising from effector T cells. The authors further identified a DNA methyltransferase called Dnmt3a which regulates T cell differentiation 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 arise 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 memory T cell formation. This new finding sheds light on better vaccine design strategy. In addition, it contributes to the improvement for immunotherapies targeting Dnmt3a.

Reference

• 'Rama S. Akondy, et al.' Origin and differentiation of human memory CD8 T cells after vaccination. Nature. doi: 10.1038/nature24633.
• 'Ben Youngblood, et al.' Effector CD8 T cells dedifferentiate into long-lived memory cells. Nature. doi: 10.1038/nature25144.