What are memory T cells, what do they do, how have they been used by humans and where do they come from?

T lymphocytes or T cells are cells which are part of the immune system and play a major role in the immune response. T cells are produced in the lymph nodes and released into the bloodstream. There are 3 main types of T cells: naïve T cells, effector T cells and memory T cells. Naïve T cells are T cells which have not previously encountered a pathogen and are awaiting their first encounter. When a pathogen is recognized, naïve T cells rapidly multiply and express molecules such as cytokine proteins to help combat the infection. T cells in this active immune response state are known as effector T cells (more specifically cytotoxic T cells [a subtype of effector T cells]). These effector T cells can migrate to inflamed tissues and kill infected cells. However, once the pathogen is fully eliminated, most of the population of effector T cells in the body dies out. Nevertheless, a small number of long-lived memory cells remains with the purpose of enabling a rapid secondary immune response should the pathogen be reencountered. These cells are called memory T cells. Memory T cells can be divided into two main categories: CD4+ memory T cells and virus-specific CD8+ T cells. The names are given according to the antigen proteins found on the surface of the T cells: CD4 or CD8. Memory T cells have the ability, to quickly change the epigenetic modifications of their DNA, throughout their genome and rapidly divide (turning into effector T cells), if a known pathogen is reencountered. Not all memory T cells are the same, some circulate through the bloodstream and the body, waiting for pathogen reencounter, whereas tissue-resident memory T cells reside in tissues such as the lung, skin and gut, providing a first line of defense against reinfection at sites where pathogens often enter the body.Moreover, scientists are still in debate over which cell type the memory T cell population arises from: the naïve T cell, or the effector T cell population.

There are two main theories regarding the formation of memory T cells. The first, proposes that memory T cells arise from a small subset of effector T cells which manage to escape death after the pathogen is eliminated. The second proposes that memory T cells arise directly from naïve T cells, potentially as early as their first division, giving rise to either effector T cells or memory T cells. Recently, two studies attempted to resolve this debate by tracking virus-specific CD8+ T cells during the course of an infection. One of the studies studied people who had received a yellow fever virus vaccine, whereas the other group of researchers worked with a mouse model of lymphocytic choriomeningitis viral infection. Both studies looked at the epigenetic modifications in naïve, effector and memory T cells. Epigenetic modifications are, usually heritable, modifications to the structure of DNA, which do not alter the DNA sequence. Epigenetic modifications drive and regulate gene expression in various ways such as altering the chromatin structure (the structure of DNA along with its surrounding proteins and various modifications) and communicating with transcription enzymes and transcription-promoting or restricting proteins. One such epigenetic modification is DNA methylation. DNA methylation is the process in which a DNA methyltransferase enzyme adds a methyl group to a cytosine nucleotide. This addition of a methyl group results in heterochromatin (tightly packed chromatin environment which is hard to access for transcription machinery) and and other phenomenons associated with gene repression such as preventing the binding of transcription proteins to the DNA, and a general repression of the gene which has been methylated, fixing the gene in an ‘off’ position. One of the studies used genome-wide DNA methylation profiling to find that as naïve T cells differentiated into effector T cells, their DNA methylation profile changed. Methylation was observed to have been added to regions with genes associated with keeping the T cells in their naïve state and removed from regions with genes associated with essential effector T cell functions. The authors identified Dnmt3a (DNA methyltransferase a) as the key enzyme responsible for de novo DNA methylation (DNA methylation in previously unobserved sites) throughout the immune response. They also showed that, in effector T cells that are changing into memory T cells, the methylation of genes associated with the naïve state, can be removed in a cell-division independent process. This may potentially show, that the re-expression of naïve-state associated genes is required for the formation or maintenance of long-term cellular memory. Both studies concluded that even though memory T cells no longer express genes associated with effector T cells, these genes remain in a state of low methylation. One of the studies also confirmed that memory T cells that are present as long as ten years after a pathogen encounter or vaccination have an open chromatin environment that is comparable to that found in effector T cells. However, these genes are not actively expressed until the pathogen is reencountered, after which memory T cells rapidly divide and ‘reactivate’ the effector T cell associated genes.

This mechanism is needed for a rapid secondary immune response. It is also how ‘immunity works’. When people say ‘you can’t get _____ (a disease) twice’, what they really mean is, if you do get the disease again, upon pathogen entry, your body and more specifically your memory T cells will respond to combat the pathogen, quickly dividing and expressing effector T cell associated genes, usually resulting in few or complete lack of symptoms. Vaccination exploits this feature of the immune system by introducing a (relatively) harmless pathogen into the body, to allow for an immune response and the formation of cellular memory. The pathogen which is introduced into the body during vaccination is either very similar to the real pathogen (which the vaccine tries to stop from infecting the body) or it is an attenuated (weakened) version of the actual pathogen. This allows for the immune system to respond swiftly, building up cellular memory, without having severe effects on the body. Recently, vaccines have also come in the form of RNA (RNA vaccines). Despite the end result being the same as other vaccines, this technology is very new and perhaps a topic for discussion at another time.

Furthermore, both studies provided evidence for memory T cell formation from a population of effector T cells, repressing effector T cell associated genes and essentially ‘bookmarking’ them epigenetically, ready to re-express given genes upon pathogen reencounter. However, the studies did not exclude the possibility of a small population of naïve T cells independently differentiating directly into memory T cells.

In one of the studies, effector T cells were labeled with a heavy from of hydrogen called deuterium to track their divisions and general presence. This study later showed that virus-specific memory T cells (formed from the effector T cells, tracked by the deuterium labelling), present between one and two years after pathogen encounter/vaccination, expressed many genes associated with a naïve T cell state (derived from a cell-surface protein comparison). This supports the model in which after pathogen exposure, memory T cells stop expressing effector genes and instead express many genes associated with the naïve state, such as genes that aid T cell survival and migration.

In conclusion, memory T cells are essential for humans to survive and they prevent us suffering from many diseases over and over again. Moreover, without memory T cells we wouldn’t be able to develop vaccines to protect us against a wide variety of viral infections. It is fascinating to see this mechanism of nature at work, protecting us from all infections, where would we be without them?

References

Nature. 2017. “Effector CD8 T cells dedifferentiate into long-lived memory cells.” https://www.nature.com/articles/nature25144.

Nature. 2017. “Origin and differentiation of human memory CD8 T cells after vaccination.” https://www.nature.com/articles/nature24633.

Nature. 2017. “The origins of memory T cells.” https://www.nature.com/articles/d41586-017-08280-8.

Science direct. 2018. “Memory T Cell.” https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/memory-t-cell.