Enlarge /. T cells that attack a cell recognized as foreign.
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We are still struggling to understand whether SARS-CoV-2 infection with or without symptoms of COVID-19 will protect against further infection. Antibodies are an indicator of immunity and are the easiest aspect of the immune response to track. However, the data show that the production of antibodies varies widely and their production can begin to fade within months. However, the immune response has many other aspects, many of which focus on T cells. And here, too, the reaction seems extremely complex.
More studies are now being published that address other specific aspects of the immune response. While these results give cause for optimism about long-term immunity, there are still a large number of unknowns.
Go with the flow
The two studies we're about to look at were made possible by a technique called "flow cytometry," which has been found to be very useful in studying the immune response. It basically helps researchers overcome the biggest problem with these studies: there is an abundance of very similar-looking cells involved in an immune response. While a trained eye can tell a T cell from a macrophage with a microscope, knowing that T cells exist doesn't tell us much. Not only do we want to know how many of them there are, we also need to know what types of T cells there are. T cells can help produce antibodies, they can kill infected cells, they can be used to remember exposure to pathogens, etc.
Flow cytometry can help us determine which cells are actually there. The immune cells are taken from a blood sample and flow past sensors one after the other. Each of these sensors can look at some aspect of the cell – usually you tag the cells with a fluorescent molecule that only sticks to certain types of cells, and you use a laser to determine if the molecule is present while a cell is flowing by. After the sensor, the device can redirect the flow to separate cells with and without these molecules.
So if you make a fluorescent molecule that will adhere to T cells, you can determine how many T cells there are and separate them all. The key is that this can be done iteratively. Once you have the T cells, you can add another tag and separate a single T cell population like the killer T cells. And then you can separate certain types of killer T cells from that population. In the meantime, the other population – anything that isn't a killer T-cell – can be sorted as well, so researchers can pull out the storage T-cells, and so on.
This can give us a sense of what cells are present while an infection is ongoing. But not only that, its final output is a pure population of specialized cells that can then be examined more closely to find out what they are up to.
The more tags you can use to separate cells, the more detailed your analysis can be. In this case, the researchers had access to equipment that could do a lot: almost 30 individual tags were used to separate different cell populations. (Both works have researchers from the Swedish Karolinska Institute, which is likely to house these sophisticated machines.)
I remember it
In one article, the research team focused on figuring out what types of T cells are present in people infected with SARS-CoV-2 and what happens after the virus is cleared. In total, the researchers had samples from over 200 people and data on their clinical outcomes – they knew which people had severe cases and could possibly correlate this with the presence of certain types of immune cells.
It found that those with active infections produced many killer T cells that target and eliminate infected cells. The research team also found a difference after the infection ran its course. Here, those with mild or severe symptoms appear to have produced greater numbers of memory T cells in preparation to fight off another SARS-CoV-2 infection.
The presence of these memory T cells was not related to whether the individual was producing antibodies to the virus, suggesting that they could serve as an alternative route to immune protection. Emphasis on "power". The researchers emphasize that "it remains to be determined whether robust memory T-cell responses in the absence of detectable circulating antibodies can protect against severe forms of COVID-19". The "unknown" category also includes how long these memory cells are kept – the answer is "over a decade" for SARS and MERS.
As in other recent studies, these researchers found that T cells were ready to respond to SARS-CoV-2, even in people who had never been exposed to it, possibly due to exposure to coronaviruses who had cold-like symptoms cause. Again, it is completely unclear whether this offers any kind of protection.
T cells aren't the only ones that can kill infected cells. There is another type of blood cell called a natural killer that does too. While T cells are adaptive – they recognize a specific trait of a pathogen by virtue of a unique receptor structure – natural killers by and large recognize cells infected with entire classes of pathogens. Using the same flow cytometry equipment as in the other publication, another team of researchers analyzed what was going on with natural killers in a small population of patients with COVID-19 (both mild and severe cases).
As expected, natural killer cells had evidence that they were activated by a SARS-CoV-2 infection, producing immune signal molecules, and dividing to produce more of these cells. In this regard, however, there was little difference between patients with mild and severe symptoms. However, there were other differences that apparently correlated with the severity of the disease. Most importantly, this includes the production of the protein used to kill infected cells, which is far more common in samples from patients with severe cases. Cells from patients with severe cases also showed more evidence of involvement in an inflammatory response.
In contrast, natural killer cells from people with mild COVID-19 symptoms tended to be high in what is known as "checkpoint" protein. These proteins help shut down cells' activity when certain conditions are not met and can therefore help to weaken the response of the natural killers.
cause and effect
Unfortunately, the challenge here is to separate cause and effect. It is not clear whether a more aggressive response from natural killer cells creates the problems that result from an excessive inflammatory response and thus contribute to the severity of the disease. It could simply be that a more severe illness leads to a more aggressive natural killer response.
Overall, these two articles – and many more that continue to be published every week – offer an increasingly detailed look at the activity of the immune system in response to SARS-CoV-2. Unfortunately, the picture they paint is extremely complex and does not fit perfectly into a simple picture that could help with guidelines or treatments. T cells clearly retain memories of exposure to SARS-CoV-2, but it's not clear whether this is protective in the long run. Some immune cell types are more active in severe cases, but it is not clear if we can identify this far enough in advance to tailor treatments.
Over time, a clearer picture will gradually emerge from the accumulated evidence that each of these studies provides. This will take some time, however, and the likelihood that a single study will provide either a clear picture or a breakthrough is slim.
Cell, 2020. DOI: 10.1016 / j.cell.2020.08.017;
Science Immunology, 2020. DOI: 10.1126 / sciimmunol.abd6832 (Via DOIs).