Enlarge /. T cells that attack a cell recognized as foreign.
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Ultimately, the only way for societies to return to an appearance of normality after the current pandemic is to achieve what is known as herd immunity. Here, a sufficiently large percentage of the population has acquired immunity to SARS-CoV-2 – either through an infection or a vaccine – against which most people who are exposed to the virus are already immune. This means that the infection rate slows down and eventually fails, protecting society as a whole.
Since this is our primary goal, we need to understand how the immune system responds to this virus. Most of what we know is based on a combination of what we know about other corona viruses that infect humans and the antibody response to SARS-CoV-2. However, data on the response of T cells are now available, indicating that their response is more complex: longer lasting, broadly based, and associated with an overlap with the response to previous coronavirus infections. What this means for the prospect of permanent protection remains unclear.
What we know now
SARS-CoV-2 is one of seven coronaviruses known to infect humans. Some of them, like SARS and MERS, have only recently made the leap to humans. While we are more lethal than SARS-CoV-2, we are lucky that they spread less efficiently among people. These viruses appear to elicit a long-lasting immune response after infection. This is a sharp contrast to the four coronaviruses that are common in humans and cause cold symptoms. These viruses induce immunity that appears to last less than a year.
We don't know much about the immune response to SARS-CoV-2 yet. Monitoring antibody production shows that many of the infected have a robust immune response, but "many" are far from "everyone" – the extent of the response varies widely. This variability is associated with a huge difference in the severity of COVID-19 in patients. One area of concern is that the antibody response to SARS-CoV-2 appears to be rapidly decreasing.
However, the antibody response is only part of the immune system's defense against a pathogen. Antibodies typically recognize the proteins that are on the surface of a virus because they are the ones to which the cells that produce antibodies are exposed. A second group of cells, called T cells, recognizes pathogens in a different way. T cells are based on a system that is used by all cells. It takes small pieces of the proteins they produce and presents them on the cell surface. Because of the way the system works, it may be able to recognize more proteins from a virus – not just those on its surface.
(Some immune cells that swallow pathogens also bring protein fragments to their surface in the same way.)
There, all T cells that recognize these small pieces of protein as foreign can trigger a variety of reactions, from the activation of their immune cells to the killing of the cell that produces foreign proteins. Studying the T cell response is much more difficult because it is based on cells rather than antibodies that are proteins. However, such a study can be equally important for long-term immunity.
Studying the Ts
To investigate the T cell response, a Singapore-based group of researchers focused on proteins that are either contained in the virus or are only used in the cells it infects and therefore do not constitute a major focus of the antibody response. To test the response to these proteins, the researchers produced a set of 15 amino acid protein fragments that together span the entire length of the protein. They then collected blood cells from people who had recovered from COVID-19, from people who had recovered from the original SARS, and from people who had never been exposed to either virus.
These fragments were pooled and mixed with blood cells to determine if any T cells in them responded to them. By narrowing the pools, the researchers were able to identify the specific fragment – and thus the specific region of the protein from which it came – to which T cells responded. The answer was registered by checking the level of an immune signaling molecule produced by T cells.
One of the potentially reassuring findings was that people who had been exposed to the original SARS virus 17 years earlier still had T cells that responded to fragments of the virus. This was true, although the antibody response to this virus generally faded after a few years. Not surprisingly, people who recently had COVID-19 also had T cells that responded to fragments of the virus proteins.
However, there was one striking feature of the SARS and COVID-19 fragments that the T cells responded to: many of them were identical. While SARS-CoV-1 and -2 are different viruses with different histories, many of their proteins remain extremely similar. (This is probably because they continue to perform similar functions and therefore there is evolutionary pressure against change.) As a result, some of the fragments made from the SARS-CoV-2 proteins were in the equivalent protein from SARS identical to -CoV-1. A T cell that recognized one of these fragments was able to recognize both viruses – even though it came from a patient who was only exposed to one.
This creates the conditions for the most surprising result of the study. Participants who had never been exposed to any of the SARS viruses also had some T cells that recognized parts of SARS CoV-2 proteins. This did not apply to every participant in the unexposed group. only about half of them had these reactive T cells. But again, it was mainly based on cells that responded to pieces of protein that were identical between SARS-CoV-2 and viruses that cause colds.
Mostly, but not all. There were two exceptions – two protein fragments that didn't look like the common cold virus, but caused a response from T cells of unexposed participants – and the researchers are trying to explain them. Your only suggestion is that another pathogen happens to have a small portion of the protein that looks like it. There were also differences between the groups of which of the three proteins recognize their T cells, but the meaning of these differences is not clear.
What does it all mean?
So does this mean that the cold can potentially protect some of us from COVID-19? There is no way to know from these results. Previous exposure to cold-causing coronaviruses appears to induce a response to other proteins than exposure to SARS-CoV-2. And there is no evidence that antibodies to cold viruses cross-react with SARS-CoV-2. Would a T cell-based response alone be enough to fight off the virus? We do not know it.
At the same time, the fact that this reaction only occurs in a subset of people who have never been exposed may explain some of the differences in the severity of COVID-19 symptoms. There is obviously still a lot to do here.
The importance of T-cell-based immunity is also critical to understanding the problem of the apparently very variable antibody response and the evidence that it can fade quickly after the SARS-CoV-2 infection has subsided. This study shows that T cell responses are consistent and strong in this small population. The parallel work on SARS patients shows that this reaction also lasts much longer than the antibody-based immune response. So if it is enough to provide protection against re-infection, we may be less concerned about the irregular antibody response. Again we don't know yet.
This could also affect the development of vaccines, which usually focus on the production of neutralizing antibodies.
All of this implies that there is an urgent need to better understand the T cell response to SARS-CoV-2. Which is unfortunate considering how difficult it is to study T cells.
Nature, 2020. DOI: 10.1038 / s41586-020-2550-z (About DOIs).