Investigating T cell Immune Response to SARS-CoV-2

This post was reviewed by Dr. Emily Bowman, one of our subject matter experts.

The paper we’re demystifying today can be found here, if you’d like to tag along!


Researchers investigated the immune system’s T-cell response to the SARS-CoV-2 virus in people who were completely unexposed to COVID-19, people who were exposed to COVID-19 but not infected, and people who had acute or convalescent COVID-19 infection. They found that during the convalescent phase of infection, the T cells specific for the SARS-CoV-2 virus showcased stem-like memory (this means they have the ability to self-renew). T cells specific for SARS-CoV-2 were also detected in exposed people who tested negative for antibodies. These people either had mild symptoms or were asymptomatic. This study suggests that broad and highly functional memory T cells are made in response to SARS-CoV-2 exposure which could possibly mean that exposure or infection could prevent a recurrence of COVID-19.


Getting COVID-19 is not fun. Doctors and researchers have documented how the excessive inflammation can result in respiratory failure and septic shock (massive bacterial infection). More often than not, though, many people who catch SARS-CoV-2 remain asymptomatic or have mild symptoms of COVID-19. The scientists in this study wanted to investigate whether milder forms of COVID-19 result in a good and strong memory immune response to SARS-CoV-2 infection.

There was limited prior evidence of reinfection for people who were previously documented with having COVID-19. There’s also data to suggest that, in rhesus macaques (a type of monkey), being infected with SARS-CoV-2 can lead to a near-complete immunity from the virus! What wasn’t understood, however, is the actual immune system mechanism that results in long lasting immune protection after getting infected with SARS-CoV-2. Many studies published before this one looked at antibody response as a way to figure out if someone is immune to COVID-19 or not. However, antibodies often aren’t detected in patients, especially patients who had a milder response to COVID-19.

As mentioned, scientists have already identified that humans produce T cells against SARS-CoV-2, but we are not entirely sure which aspects of the T cell immune response we are getting. To figure this out, these scientists took the time to properly characterize the specific helper and killer T cells that arise from SARS-CoV-2 infection. Let’s dive into what they discovered.


The first thing this team of scientists looked at was the T cell perturbation (this is essentially activation of the T cells from SARS-Cov-2 infection). Initially, they saw that the numbers of killer T cells and helper T cells were low in patients who had an acute or severe COVID-19. The team decided to take a closer look at all the different variations of T cell perturbation, by using flow cytometry. They compared T cells from two groups:

 1. Healthy blood donors

 2. Individuals who recovered from mild COVID-19.

Flow cytometry as a technique has actually been around since the 1950s. The modern flow cytometer works by sending a thin stream of cells past the instrument’s laser at very high rates- 10,000 or more cells per second. Flow cytometers can give information on the size or the granularity (overall complexity) of the analyzed cells. The real power of flow cytometry comes into play when you get into fluorescently tagged probes. A scientist can stain a cell sample with a special antibody designed to bind to a specific cell surface protein (for example, the CD4 receptor on the surface of T lymphocytes). This antibody can then be tagged with a fluorescent marker. This helps scientists separate various cell types that might be in the same sample, like different types of blood cells.

Statistical analysis from the flow cytometry results showed there was a clear difference between memory T cells from healthy donors and recovered individuals. They also saw that memory killer T cells from individuals who had acute moderate or severe COVID-19 expressed a particular cluster of immune system markers that are needed to activate and promote cell growth in T cells. A similar pattern was seen for helper T cells in these individuals as well.

Essentially the scientists suggest that having these activation markers expressed on T cells can potentially mark an earlier and more robust adaptive immune response to COVID-19.

Next these scientists stimulated peripheral blood mononuclear cells (which include the total T cell population) from patients with acute, moderate, or severe COVID-19 by taking components from the SARS-CoV-2 virus and mixing it with blood samples to trigger the immune response. By doing this, they saw that a lot of helper and killer T cells were activated and actively making more cells. They saw that many special types of killer T cells (known as tetramer killer T cells) were active in the acute stage of infection, but those same killer T cells were not active in the convalescence stage of infection. The convalescence stage of infection is the stage where one begins to recover from a SARS-CoV-2 infection.

So, they saw that early killer T cells specific to SARS-CoV-2 were expressing immune activating molecules, inhibitory receptors, and cytotoxic molecules. However, in the convalescent phase, the killer T cells were more skewed to markers of early differentiated memory T cells. This suggests that following exposure to SARS-CoV-2, a rise in stem-like memory killer T cells for SARS-Cov-2 happens over time.

So, because they knew this, it was important to see what kind of memory T cells response specific to SARS-CoV-2 there are in five different groups:

  1. Healthy people who donated blood before the pandemic
  2. Healthy people who donated blood during the pandemic
  3. Family members who shared the house with convalescent individuals
  4.  People exposed to the virus at the time of symptomatic disease 
  5. Those who were in the convalescent phase after mild or severe COVID-19.

The scientists found cross-reactive T cells responses to the spike glycoprotein of the membrane proteins of SARS-CoV-2 in group 1, which was consistent with previous studies. The highest response to different protein components of the SARS-CoV-2 virus was seen in individuals who experienced severe COVID-19 (with 100% of individuals who had a T cell response), followed by lower responses from those who had mild COVID-19 (with 87% of individuals who had a T cell response). Those in group 2 and group 3 had T cell responses too with 67% and 46% responses respectively.

The final thing to look at was the recall capabilities of specific helper and killer T cells in the different groups. The responses of specific helper and killer T cells were detected in almost everyone in group 1 and in a majority of people in group 3. Helper T cell responses to specific proteins from SARS-CoV-2 were much larger than the killer T cell response. The serological evaluations also showed that there was a strong positive correlation between antibody, IgG responses that respond to different SARS-CoV-2 proteins.

Interestingly, even people who don’t have antibodies to SARS-CoV-2 may still be able to generate helper and killer T cell responses! That being said, these responses are at lower levels in comparison to those who have antibodies. In the end, the responses were strongest in convalescent individuals who had mild COVID-19, in exposed family members, and in healthy people who donated blood during the pandemic. They also noticed higher levels of T cell responses in exposed family members who didn’t have antibodies when compared to non-exposed people.

What this indicates is that people can still have some T cell immune responses to SARS-CoV-2 even if they don’t have antibodies circulating in their bloodstream.


By using a systematic approach to identify the immune response to SARS-CoV-2 in different groups of patients, the scientists found that those who recovered from mild COVID-19 have robust memory T cell responses up to months after infection, even when they don’t have antibodies.  

They found that T cell activation is a hallmark of acute COVID-19 and that these cells express specific markers indicating that recovery from acute COVID-19 results in an early strong immune response to SARS-CoV-2. What’s really neat is that this was also seen early after immunization with successful vaccine candidates. Generally, SARS-CoV-2 specific T cells also acquire early differentiated memory types in the convalescent phase. There was a T cell response that recognized both the spike, membrane, and nucleocapsid of SARS-CoV-2, even in people who did not have detectable levels of SARS-CoV-2 antibodies. 

What this essentially implies is that looking at whether you have antibodies for SARS-CoV-2 or don’t (known as seroprevalence) may underestimate the extent of population level immunity to SARS-CoV-2. 

The scientists acknowledge that there were some limits to their study. Namely, they did not do a lot of clinical follow up and overall donor numbers were small. The researchers state that it still has to be determined whether a robust T cell response without circulating antibodies can protect from severe COVID-19. That being said, they do note that antibody levels normally drop after a certain amount of time and this is seen in every different type of coronavirus infection (from the common cold ones to SARS-CoV-2). They also say that because we see memory B cells and robust memory T cells form after a SARS-CoV-2 infection, there may be enough immunity to protect against re-infection.

In the end, this study provides some data on the various types of specific T cell immunity one can get from exposure without evidence of infection, infection with SARS-CoV-2, and from COVID-19 disease. Additionally, some pre-existing immune responses could have been potentially induced by past exposure to other related coronaviruses.  The fact that individuals with asymptomatic or mild COVID-19, and individuals exposed to SARS-CoV-2, can generate a functional and high amount of SARS-CoV-2-specific memory T cell responses is promising. What’s neat is that the scientists say that this could suggest that natural exposure or infection may prevent a recurrent episode of severe COVID-19.

BUT! In absolutely no circumstances should you go and get yourself sick on purpose. You won’t know what kind of immune response you’ll get, how severe the acute infection may be, the long-term consequences of infection, or whether you’ll end up in the hospital in critical care. In fact, we still don’t have a full understanding of what the long-term consequences of COVID-19. Many of us view COVID-19 as a respiratory illness, and it is; but researchers are finding that SARS-Co-V-2 could also be affecting other organs in our body, like our heart and kidneys. In the end, wear your mask, stay safe and it’s still best to wait for a vaccine to provide you with the immunity you need.

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