Memory against infections, against SARS-CoV-2

The maintenance of cells with a proven record after an infection is one of the pillars of the adaptive immune system. It is, one could say, the most key role of the adaptive immune system.

The cells of the adaptive immune system are B and T cells. Both cell types make their own receptors with which they can recognize pathogens. Importantly, these receptors are not directly found in your DNA. You do not inherit them from your parents, like you do with receptors from innate immune cells. Adoptive immune cells make their specific receptor in a complex way of cutting and pasting gene parts, adding and deleting pieces at random, to eventually end up with a receptor.

Extremely important is that each cell, for understanding the basics, harbors one receptor. That is, one receptor is eventually encoded for that cell, the cell will have many of these present on its surface. Making receptors at random has huge advantages, no matter how new a pathogen is, how much it changes, you will always have some cells that will recognise that pathogen. This is extremely powerful. The billions of T and B cells can collectively really recognise everything!

But, making receptors at random has pitfalls. Many are not of use at all, the worse that cannot be of use do not become part of the collective repertoire in your body. Others will recognise parts of you! That can give autoimmunity, and hence cells with such receptors will also be negatively selected to die and not be part of the circulating cells in your body. It still leaves billions of cells.
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Yet, the vast majority of those are also not of immediate use. The motifs (antigens) they recognise you may never encounter, and hence the turnover of T and B cells is high. Many die every day; you generate many new ones to replace these. This goes on till old age, although the rate of new cells added is slowing down with age.
 
Helpful review here.
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There is another problem; you have billions of cells, but few that recognise a given pathogen. This is the reason that adaptive immunity is slow, 10-14 days until it is a bit up and running, with maturation of it that can take many months. Maturation is in large part the refinement of the response, making increasingly better antibodies by, at random, mutating the B cell receptor genes. The B cell receptors, when secreted, are called antibodies. By mutating the antibodies, and a complex system of different B cells competing for the same antigen, there is a process of mini evolution going on in your lymph nodes. The result is antibodies with an incredibly high affinity and specificity.
 
Those T and B cells that do recognize a part of a pathogen, and help you clear it are unbelievably valuable. These have proven that they recognize a pathogen you have encountered and can get infected with again in the future. Hence, you really want to keep those! These cells will become part of your memory compartment. This compartment is independently regulated from all those cells that have never encountered the antigen they have a receptor for (the naïve cell compartment). The size of the memory compartment is also not infinite, regulated by physical space and survival cytokines such as interleukin-15. This does mean that there will be some loss over time. Unfortunately, this loss is the highest in old age. This, combined with a reduced naïve compartment, makes the elderly more susceptible to infections. Any infection.

The fact that memory cells can recognize a pathogen that you may encounter again is useful. But that is only part of the story. Remember the billions of naïve cells, most with a unique receptor. You have very few that recognize the same antigen. In the memory compartment you save many with the same specificity. So, you start the next infection with many more cells to rely on. This will give you much advantage to contain and clear the pathogen. In addition, memory T cells adhere to different rules. They can be activated much quicker. They migrate to the site of infection fast, within a day often. Many are already there and patrol the regions where you first encountered the infection! Their functional capacities do not need to mature, the transcriptional program is already determined and active: the result is an extremely fast response, a day or 1-4, well worth keeping!
 
 
How do we know about memory cells?
Many experiments and studies have been performed over many decades to gain many insights about memory cells. A lot, on the molecular and cellular level, has been done in laboratory animals, especially mice, but also rats and non-human primates. In humans, many of these obtained insights have been reproduced and observed to hold very well. I will give a brief overview.
 
Some good examples here show the existence of a memory compartment in humans, with effector functions, as initially obtained from mouse studies. These cells have many of the same molecules on their surface (markers) by which immunologists can recognize and classify the memory cells and study their functionality. 
 
Here you see what happens if you activate naïve T cells (a) and see how much of the important cytokine IFNg they make, compared with memory T cells (b) at the same time.

A particularly helpful review of the state of the field in 2004, can be found here.
 
In human we can find memory cells against many of the pathogens that regularly infect us, such as Candida albicans and Mycobacterium tuberculosis, Hepatitis C virus, HIV and CMV, and of course many others such as those vaccinated against. Influenza is a prime example where elderly respond weaker, due to a complex array of issues that hamper immune responses. Therefore, is a vaccine so important, to prepare much better for any potential infection. However, not everyone will respond robustly enough.
 
Also, antibodies can easily be detected in blood. Although their levels drop and active production may come to a near halt, a boost will very rapidly increase these to extremely elevated levels: it is the memory B cells that are responsible for this. This can be done for all vaccines for example. With some especially relying on this response to provide disease protection even after contact with a pathogen (e.g., Tetanus).
 
COVID-19
There are stories circulating on social media to cause confusion about our protection against SARS-CoV-2. Some people, even several that should know better, make claims of uncertainty about the memory we build up against SARS-CoV-2 and how long it will last. Claims are accompanied by false statements about not knowing how memory T cells are maintained and the absence of data on memory cells from other infections.

This is shameful; there is no reason to assume SARS-CoV-2 is dramatically different from all those pathogens, it has not behaved particularly different to most other pathogens. 

https://www.thematic-ai.eu/prof-marc-veldhoen/sars-cov-2-new-and-familiar 

Furthermore, we know that memory cells last an exceptionally long time. First, the vaccine and the virus will generate an immune response. An immune response severe enough to recruit B and T cells, to activate them, and hence, to generate a memory response. We know all of that, it was tested in mice and non-human primates. 
 
Of course, it was confirmed in humans. In September 2020, very good T and B cell response. Subsequently a flurry of papers showing good B and T cell responses and memory responses.

https://www.nature.com/articles/s41586-021-03791-x
https://www.nature.com/articles/s41564-022-01106-y
https://www.science.org/doi/10.1126/scitranslmed.abi9915
https://www.science.org/doi/10.1126/sciimmunol.abm8389
https://www.science.org/doi/10.1126/science.abm0829
https://www.science.org/doi/10.1126/sciimmunol.abl5344
https://www.sciencedirect.com/science/article/pii/S0092867422000769
 
Memory cells have been studied over time in humans too. The most famous is the response after the Spanish flu in 1918, with memory B cells still capable of producing neutralizing antibodies detected in 2008, 90 years later! And of course, SARS is the most recent example of a similar virus, present at least 17 years later. 
 
And we know, these cells respond quickly. B cells make antibodies very rapidly, memory T are recruited to the site of infection and do make all the difference to contain and clear the virus. 
 
In other words, SARS-CoV-2 has provided us with immunology in real time. It has once more confirmed all those principles and aspects of our immune system we have been studying for decades. It is a textbook virus with a textbook response. This also counts for the memory response we generate, maintain, and will rely upon successfully to fight SARS-CoV-2 infection.