Killer T-cells: How they protect you from COVID-19

DUBAI: The human body is a complex system. At its best form, the body has its own ability to fight off diseases.

It's a constant battle, waged between the human body's natural “antivirals” and pathogenic invaders (like SARS-CoV-2).

For the most part, this constant search-and-destroy action takes place without us knowing (almost) about it. Until symptoms like fever, cough, lethargy, or worse, show up.

Vaccines, which train our immune system against specific disease-causing agents, are also known as “antiviral therapeutics”.

T-cells: Natural antivirals

In the face of SARS-CoV-2, the deadly pathogen that causes COVID-19, the world desperately needs a vaccine (or vaccines), and fast.

Infections are still spiking, with an 214,000 cases in the last 24 hours. Out of the 15 million confirmed cases so far (as of July 22, 2020), more than 8.47 million recovered. There had been over 617,000 deaths reported.

It appears that more than 95% of those who contract the virus survive. And this is thanks, in no small part, to the body's "killer" T-cells.

However, the journal Nature noted that not much is known about the presence of pre-existing "memory" T cells in humans with the potential to recognize SARS-CoV-2. To find out, a team led by Nina Le Bert of Duke-NUS Medical School, Singapore, studied T-cell responses in humans with the potential to recognise the coronavirus.

Specifically, the team studied T-cell responses to structural protein (known as nucleocapsid protein, NP) and non-structural protein (NSP-7 and NSP13 of ORF1) regions of SARS-CoV-2 in 36 people who recovered from COVID-19. 

Here's what they found: In all of them, the team demonstrated the presence of "CD4" and "CD8" T-cells recognising multiple regions of the neocapsid protein in SARS-CoV-2.

The coronavirus nucleocapsid is a structural protein that performs a number of functions and plays a key role in enhancing the efficiency of viral multiplication.

Cross-reactivity

Then there's the surprising "cross-reactivity" bit: The Singapore researchers showed that 23 patients who recovered from the previous SARS pandemic (in 2003) still possess long-lasting memory T cells reactive to SARS-NP — a total of 17 years after the SARS outbreak.

This, the researchers said, shows the "robust" cross-reactivity to SARS-CoV-2 neocapsid protein. Surprisingly, in 37 patients with no history of SARS or COVID-19, the team also detected SARS-CoV-2 specific T-cells.

Another research team, this time in Germany, also conducted research to find out something more fundamental: which part of our natural antivirals (T-cells) actually work against what part of the novel coronavirus?

Neutraliser

Knowing the answer to this question is vital. For one, it would it help vaccine makers. Two, it would help explain the great number of COVID-19 patients who had mild cases and had recovered.

Three, and more impotantly, it would also help determine which areas or components of the virus — known as “epitopes” (the bad guys within the virus) — attract our natural antivirals enough to trigger an immune response.

In humans and other vertebrates, the key to this response are the antiviral “T-cells”, whose job is to neutralise, or “kill” virus-infected cells.

The immune system is a complex web of organs containing cells that recognise foreign substances — and destroy them. In general, it protects vertebrates against pathogens (infectious agents) such as viruses, bacteria, fungi, and other parasites.

Immunologists now are targetting these foreign substances at the epitope (sub-unit of antigen) level.

Knowing the character of viral T-cell epitopes (components of a virus that stimulate T-cell action, and trigger an immune response) is crucial.

At the very least, it would boost scientists' understanding of the inner workings of our immune defense mechanism.

Focus on T-cell epitopes

Scientists have great interest in identifying epitopes in antigens. More specifically, they are interested which epitopes are recognized by B- and T-cells.

For one, it advances the medical community’s understanding of diseases, immune monitoring, developing diagnosis assays and designing epitope-based vaccines.

Epitope identification, however, is both costly and time-consuming: It requires clinical screening of large number of potential epitope candidates.

Now, armed with computer algorithms, scientists made a razor-sharp focus on T-cell epitopes in the coronavirus to predict which specific epitopes of SARS-CoV-2 trigger T-cell response in infected humans.

German researchers led by Annika Nelde sought to confirm their computer-generated predictions. On June 16, 2020, they published a pre-print of their study in Research Square.

The team, made up of more than 20 scientists working in German hospitals and universities, including the Natural and Medical Sciences Institute at the University of Tübingen, conducted a clinical study.

They used blood samples from two groups of people: 180 individuals previously infected with SARS-CoV-2 and 185 individuals not exposed to the virus. And that's how they measured the response of T-cells. 

T-cell epitopes

The German team found out that some viral epitopes were specific to SARS-CoV-2 (the epitopes were not found in any other pathogens).

This discovery is fundamental: it’s the first work that identifies and characterises SARS-CoV-2-specific T-cell epitopes among BOTH those who recovered from COVID-19 (convalescents), well as unexposed individuals.

Besides confirming the relevance of T-cell epitopes for immunity, the findings also help scientists better understand the course of COVID-19 infections.

Another significance: it shows how SARS-CoV-2-specific T-cell epitopes enabled detection of post-infectious T-cell immunity, even among those who recovered that are “seronegative” (yielded a negative result in a blood test, i.e. virus is not present).

Moreover, they found other epitopes that are “cross-reactive” — they were similar enough to epitopes on viruses that cause common-cold to prompt a T-cell response.

Other key findings:

■ 81% of unexposed individuals had some T-cell response to these epitopes.

■ This suggests at least some built-in immune protection from SARS-CoV-2.

■ T-cell responses in previously-infected people were much more “robust” than those in unexposed individuals.

■ Individuals with a broader T-cell response to viral epitopes (from SARS-CoV-2) reported less-severe COVID-19 symptoms.

The researchers stated: “Intensity of T-cell responses and recognition rate of T-cell epitopes was significantly higher in the convalescent donors compared to unexposed individuals, suggesting that not only expansion, but also diversity spread of SARS-CoV-2 T-cell responses occur upon active infection.”

“Whereas anti-SARS-CoV-2 antibody levels were associated with severity of symptoms in our SARS-CoV-2 donors, intensity of T-cell responses did not negatively affect COVID-19 severity,” they added.

Why is this study important?

■ The study found that there's less-severe COVID-19 symptoms in individuals with broader T-cell response to SARS-CoV-2 viral epitopes.

■ In the case of patients with milder symptoms of COVID-19, the researchers found a wider diversity of SARS-CoV-2 T-cell responses.

■ This, the researchers believe, suggests that people with some T-cell recognition of SARS-CoV-2 prior to infection may exhibit less severe illness.

■ Moreover, they also pointed out that this offers one clear evidence that the development of immunity requires recognition of multiple SARS-CoV-2 epitopes.

■ Both the specific as well as cross-reactive SARS-CoV-2 T-cell epitopes identified in the study enable the identification of “heterologous” and post-infectious T-cell immunity.

■ Eventually, the researchers believe the discovery would facilitate the development of diagnostic, preventive, and therapeutic measures for COVID-19.

Antigens vs antibodies: What’s the difference?

ANTIGENS are molecules capable of stimulating an immune response. Each antigen has distinct surface features, or “epitopes”, resulting in specific responses.

ANTIBODIES (immunoglobulins, or Ig) are Y-shaped proteins produced by B-cells of the immune system in response to exposure to antigens. Each antibody contains a “paratope” which recognizes a specific “epitope” on an antigen.

What’s next?

For this study, the team said more research needs to be done by comparing the same subjects before and after infection. This could then help scientists understand how T-cell “cross-reactivity” relates to immunity and the severity of symptoms.

Nevertheless, they said, the study suggests that promoting T-cell responses to SARS-CoV-2 may be important for designing effective therapeutic and preventive measures, including vaccines.