T Cell and Innate Immune Responses to Viral Infection – Implications for the Pandemic

While much of the focus on treating COVID-19 and preventing its spread has been on antibodies, emerging research is indicating that T cells of the adaptive immune system are equally important to not only disease resistance and vaccine development but also to epidemiological tracking. Researchers at Karolinska Institute assert that recent T cell immunity testing done in a study there reveals that the number of COVID-19 cases is about double what estimates made based on earlier seroprevalence antibody testing had indicated. Results just released from a T cell immunity study from Germany suggests that perhaps 80% of the population may carry COVID-19 resistance acquired from exposure to some of the other four coronaviruses that cause common colds. If correct, such results have clear implications for achievement of more accurate estimates of both infection lethality rates and of timeframes for achieving herd immunity with and without a safe and effective vaccine. The high degree of COVID‑19 resistance in those too young to benefit from either antibodies or T cells is also discussed.  

Immune System Background

The mammalian immune system is composed of two parts: the evolutionarily more ancient innate immune system and the more advanced adaptive immune system. The adaptive immune system is the component that generates antibodies and maintains a memory of pathogens against which these antibodies were made. Viral infection triggers a different immune response than does infection by bacteria or the presence of toxins. Viruses can be detected in the blood stream by various elements of the innate immune system including dendritic cells. Although they develop branched projections (dendrites) similar in appearance to those produced by neurons, dendritic cells are not neuronal. These cells vigilantly sample their surroundings for non-self antigens. Once in contact with a potential pathogen, they phagocytose it and degrade its proteins into antigen fragments that are combined with intracellular major histocompatibility complex (MHC) molecules. These complexes migrate to the cell surface and the dendritic cells move to lymph nodes. There the antigens presented on their surfaces trigger the coordination of pathogen-specific immune responses of the adaptive immune system via the activation of antibody-producing B cells and of two types of T cells. 

Antibodies garner much of the press

Much of the attention in media coverage of the COVID-19 pandemic has gone to antibodies, and deservedly so. These molecular reagents produced by B cells in response to COVID-19 infection are exquisitely designed to target the SARS-CoV-2 virus specifically. Antibodies generated in response to a safe and efficacious vaccine could block viral infection after pathogen exposure as effectively as previous contact to the actual virus. Different types of antibodies are produced to combat the infection. Some bind to infected cells as a signal to other elements of the immune system to destroy these cells and the replicating viruses they contain. Others function to neutralize the virulence of circulating virus particles by knocking out their ability to enter cells and replicate. Researchers are combing the serum of subjects who have recovered from COVID‑19 to source top-performers from this second class for production as monoclonal antibodies (MAbs) to treat those already infected. An effective neutralizing MAb would not allow virus particles to enter cells, thereby preventing them from replicating and spreading the infection in the body. Another important aspect of anti-SARS-CoV-2 antibodies is the ability to detect them in the blood of persons who have recovered from a prior infection, even one that was asymptomatic. In this way, antibodies allow epidemiologists to better track the spread of the virus through a population.

Antibody binding assays are a particular expertise of MarinBio, whether accomplished by precise and quantitative molecular methods such as ELISA or in sophisticated cell based immunoassays. 

Role of T cells in combatting viral infections

However, while the role of T cells in the body’s reaction to COVID-19 infection has been covered less prominently, these cells are increasingly seen to play key roles in the immune response to the SARS-CoV-2 virus. Cytotoxic T cells, also called killer T cells, seek out infected cells marked by MHC/viral antigen complexes on their surfaces that have escaped detection by antibodies. Like the memory B cells that produce antibodies, some T cells also have a memory and can be ready to quickly spring into action in the future if the same pathogen is again detected. Training cytotoxic T cells to recognize viral antigens is also a key component of vaccine design when antibody protection alone may not be sufficient to prevent infection. An even more important class of T cells may be the T helper cells, as these are not only essential for the activation and growth of cytotoxic T cells but are also required for stimulating B cells to secrete antibodies. 

Using T cell responses to gauge spread of COVID-19 in populations

In a recent study on T cell-based immunity from Karolinska Institute in Sweden, over 200 subjects comprising those previously diagnosed with COVID-19 (many with mild/no symptoms), their exposed asymptomatic family members, and healthy blood donors from 2020 were checked for both anti-SARS-CoV-2 antibodies and for T cell responses consistent with earlier COVID-19 exposure. A control group of healthy 2019 blood donors was also included. In addition to those with verified infections, many of the asymptomatic family members showed T cell immunity, along with 30% of the healthy blood donors, a portion considerably higher than indicated by earlier seroprevalence studies. The researchers concluded that about twice as many persons in the population had developed T cell immune responses to SARS-CoV-2 as had been estimated from antibody testing results, and that this outcome should apply to any country, with clear implications for epidemiologists tracking the spread of the virus. While the study provides no information on whether a strong memory T cell response to COVID-19 infection in the absence of detectable circulating antibodies could block the virus from getting established, it is reasonable to assume that, analogous to the situation with partial immunity conferred by influenza vaccines, any infection would at least be less severe.

Cell based immunoassays developed by MarinBio for in vitro platforms or flow cytometry exploit the extreme specificity of B/T cell receptors to detect and quantify inhibition or stimulation of immune responses in biological samples. 

Cross-reactivity of COVID-19 T cell immune responses to other coronaviruses

SARS-CoV-2 is the fifth coronavirus known to be transmissible between humans. The other four coronaviruses are responsible for about 20% of common colds. This fact has led to speculation that developing long-term (multi-year) immunity to SARS-CoV-2, either by vaccination or actual infection, might not be possible. On the other hand, short-term immunity acquired to other coronaviruses might confer some level of COVID-19 resistance to persons never previously exposed to SARS-CoV-2. Although the detection and evaluation of T cells specific to a viral infection is technically demanding and not as straightforward as measuring antibodies by immunological tests like ELISAs, a recent study at University Hospital Tübingen in Germany sought to assess levels of T cell-based immunity to SARS-CoV-2 that might exist in the general population. T cell immune responses in blood samples from 365 healthy subjects, 180 who had recently recovered from COVID-19 and 185 whose samples were collected before the pandemic, shed some light on the possibility. While the convalescent samples showed the strongest T cell immune responses following exposure to the virus, just over 80% of the pre-pandemic samples also showed a reaction, indicating potential for some degree of immune protection from the virus. This result also might offer some insight into sources of the surprisingly high levels of asymptomatic cases seen in all age cohorts, particularly in healthy persons under 40.

MarinBio has a strong track record of producing assays that meet GMP/GLP/ICH guidelines to satisfy requests from the FDA for client projects in drug discovery, development, and pre-clinical or clinical studies, as well as for potency, lot release assays, and drug monitoring. 

Role of the innate immune system alone

When a person encounters a pathogen such as the novel coronavirus that now confronts humanity for the first time, there is no memory available for the immune system to draw upon. The response of the innate immune system becomes particularly important, as it takes up to a week for antibodies to the new intruder to be generated by the adaptive immune system. However, children do not have fully developed immune systems until they are about 7 to 8 years old. Therefore, one of the great mysteries about the SARS-CoV-2 virus is how incredibly resistant young children seem to be to the infection. The COVID-19 death data released by the CDC lags by about 3 weeks in terms of its totals (awaiting receipt of death certificates), but the proportions relative to age cohort have been remarkably consistent. As of this writing, only six children aged one to four years have died out of just over 100,000 total deaths in the US (0.006%), with no information on the contribution of comorbidities to these sad outcomes. Yet the likely much larger but unknown number of young children who have survived COVID-19 infection did so without the benefit of protective antibodies or T cells, only their apparently highly efficient innate immune systems. The next age cohort up, five to 14 years of age, suffered barely twice as many deaths (13; 0.012% of the US total), although, if healthy, most in this age range would have a functioning adaptive immune system. While not many at these young age cohorts died of influenza or pneumonia either over the same time period, the mortality rate for each of those diseases was many folds more than that from COVID-19. The source of this robust resistance to COVID-19 in those armed only with ancestral immunity may provide important clues to protecting the most vulnerable members of the world’s population from severe illness or death in the pandemic. And if any portion of individuals in older age cohorts retain some level of innate immunity to COVID-19 infection, this would have important implications for epidemiology. The situation demonstrates how much there is still to learn about this incredibly disruptive scourge.