Our immune systems are primed to fight off viruses. As evidence about how our bodies react to SARS-CoV-2 emerges, we look at how different immune cells work together to fend off the new coronavirus, and why T cells may play a greater role than scientists initially thought.

Many people will be familiar with the concept of antibodies that our bodies generate to fight off infection.

In the battle against the new coronavirus SARS-CoV-2, scientists have widely hailed the presence of neutralizing antibodies as the holy grail of immunity to future infections.

However, antibodies do not exist in isolation. In fact, several cells in our body have to work together before antibodies, particularly neutralizing antibodies, enter the stage.

One sub-set of T cells are crucial actors in the intricate interplay that leads to antibody production. Another type of T cell kills cells that viruses have infected.

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Now T cells are emerging as an additional route to immunity in the context of COVID-19.

But what are T cells, and why are they key players in the fight against the new coronavirus?

To understand what T cells do and their relationship with antibodies and short- and long-term immunity, we have to delve into the science of immunology.

What role do T cells play?

T cells are a type of lymphocyte, or white blood cell. The bone marrow produces them in the form of progenitor cells, and they migrate to the thymus, hence the name T cells.

There are several types of T cells.

In a recent This Week in Virology (TWiV) podcast, Dr. Jon Yewdell, who is the Chief of the Cellular Biology Section at the Laboratory of Viral Diseases at the National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, MD, gave an overview of T cells in the context of COVID-19.

Helper T cells, which some people call CD4 T cells, or CD4 helper T cells because they carry a protein called cluster of differentiation 4 (CD4) on their cell surface, surveil our bodies for pathogens.

Dr. Yewdell explained that when a virus infects a cell, there are two ways to alert the immune system of the foreign invader.

Once a virus has internalized in a cell, it travels through a series of compartments where enzymes unpack it and chop it into small peptides. Some of these peptides get picked up by Major Histocompatibility Complex (MHC) Class II molecules.

These molecules are part of our body’s toolkit for surveillance.

The MHC Class II molecules then circle back to the cell surface and present the viral peptide to passing cells. These peptides can activate CD4 helper T cells, which, in turn, play a crucial role. They allow B cells, another type of white blood cell and professional antibody producers, to make specific immunoglobulin (Ig) G antibodies to the viral peptide.

In response to this interaction with CD4 T helper cells, B cells then mature into either plasma cells or memory B cells. Plasma cells continue to make antibodies for several weeks, after which they move into the bone marrow. Here, they remain to provide long-term protection.

Memory B cells remain in the circulation or take up residence at strategic sites, as part of the body’s surveillance system. If our body contracts the same virus again, our memory B cells will recognize the viral antigen, process it, and re-present the viral antigen to a CD4 helper T cell.

What do killer T cells do? 

While the CD4 helper T cells recognize antigens presented by MHC Class II molecules, cytotoxic T cells, or CD8 T cells or CD8 killer T cells, react to peptides presented by MHC Class I molecules.

When a virus infects a cell, it hijacks the cell’s machinery to make viral proteins. But some of the peptides made during this process are diverted to MHC Class I molecules, which carry them to the cell surface and present them to other cells.

This allows a cell to signal that a virus has infected it. CD8 T cells find and kill infected cells, a key mechanism in getting rid of a viral infection.

As many viruses can replicate very quickly, this process needs to be fast to stop the virus from spreading. With the help of MHC Class I molecules presenting viral peptides on the cell surface, CD8 T cells can recognize influenza-infected cells within around 1.5 hours.

CD8 T cells can turn into memory CD8 T cells, which provide fast and long-lasting responses, should the same pathogen rear its ugly head again.

In the context of COVID-19, both CD4 helper T cells and CD8 T cells have important roles to play.

In a recent article in Nature Reviews Immunology, researchers from the Institute for Immunology at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, PA, summarized what scientists know about T cells and COVID-19 to date.

They indicate that CD8 T cell responses in people with severe COVID-19 may not be as effective as in those with a mild form of the disease. Specifically, there may be fewer CD8 T cells, and those that are present may be unable to turn into memory CD8 T cells.

They do, however, point out that not all study results fit into this narrative. In some cases, researchers saw excessive CD8 T cell responses in COVID-19 patients.

For CD4 T helper cells, the data suggest a similar pattern of potential dysregulation or dysfunction in normal responses.

“Most, although not all, patients who are hospitalized seem to mount both CD8+ and CD4+ T cell responses, and evidence points to possible suboptimal, excessive or otherwise inappropriate T cell responses associated with severe disease.”

— Zeyu Chen and E. John Wherry

“In fact, multiple distinct patterns of T cell response may exist in different patients, which suggests the possibility of distinct clinical approaches tailored to the particular immunotype of a specific patient,” they continue.

Testing for antibody and T cell responses

In many cases, scientists perform antibody tests to determine whether a person has developed an immune response to a viral infection.

This is different from a diagnostic test, which looks for viral genetic material to determine if a person currently has an infection.

Antibody tests are relatively straightforward. A recent, large-scale study in Spain used a combination of finger-prick testing and laboratory tests to establish how many people in the country had antibodies to SARS-CoV-2.

However, it is not so easy to test a person’s T cell response.

In a recent study comparing T cell responses between people who had recovered from COVID-19 and samples from people taken before the pandemic, scientists exposed T cell precursors from blood to viral peptides to see if this elicited CD4 helper T cell or CD8 T cell responses.

They then utilized specialist equipment to differentiate between the different types of cells that the precursors developed into.

As calls for more straightforward and speedier ways of testing whether people currently have a SARS-CoV-2 infection are gaining traction, scientists are also developing new ways of testing how our T cells respond to the new coronavirus.

Medical News Today recently spoke to James Hindley, Ph.D., from Indoor Biotechnologies, who is working on a simpler T cell test that scientists can use in routine laboratory settings.

“At first, we believe the primary use of this test will be for vaccine development, in order to determine whether a T cell response to the vaccine has been generated and whether that is adequate enough to be protective from infection,” Dr. Hindley explained.

He also foresees that public health bodies will be able to use the test to screen T cell responses to SARS-CoV-2. Together with antibody tests, this may allow them to establish the level of immunity in the population.

Scientists will need more data to elucidate how T cell and B cell responses fit into both the pathology and immunity to SARS-CoV-2 infection longer-term.

As the scientific community responds to the needs laid bare by the pandemic, new and innovative testing methods and large-scale collaborative studies will hopefully provide some of these answers.

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