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How do T cells respond to SARS-CoV-2, and could we target them in treatments for COVID-19?

A recent review published in the BSI’s official journal Immunology looked at current understanding of how T cells respond to SARS-CoV-2 infection in patients with severe COVID-19, and how treatments related to T cells could be of benefit.

T cell illustration

SARS-CoV-2 is a coronavirus that infects the lower respiratory tract (lungs and windpipe) and makes people ill with COVID-19. SARS-CoV-2 can enter a cell through ACE2 receptors, which are commonly found in the cells lining the lungs. The receptor also plays a role in regulating blood pressure and inflammation, so when the virus gets into these cells and stops them functioning normally, tissue damage can occur as a result.

When SARS-CoV-2 enters the body, the innate immune response is usually the first way of trying to clear the virus. This response involves many different types of cell, some of which release cytokines – these molecules signal to the other cells that they need to start fighting back. One type of cytokine called interleukin-2 helps to activate the adaptive immune response, which is much more specific and targeted, but can also promote inflammation. Scientists are starting to learn that a successful transition from innate to adaptive responses is linked to less severe cases of COVID-19.

The immune response to SARS-CoV-2

SARS-CoV-2 infects cells in the lining of the lungs, causing them to release cytokines, which can lead to inflammation and fluid build-up (pulmonary oedema). Researchers have found that T cells of some patients who had severe COVID-19 did not seem to be as responsive to the virus as those who only had moderate symptoms. There is also evidence that the lung damage seen in some patients with severe COVID-19 could be because the cells lining the lungs and immune cells are causing high levels of inflammation, as well as large amounts of immune cells entering the lungs.

The innate and adaptive immune responses can work together to fight off SARS-CoV-2 in most cases. T cells have a key role in promoting antibody production and targeting virus infected cells for destruction. On the other hand, there is more chance of lung damage if the innate immune response is overactive and the adaptive response is underactive, either by lack of T cells or because those present don’t function well. Overactivation of immune response can also lead to accumulation of immune cells in the lungs. As a result, some patients who had severe COVID-19 had low numbers of T cells in the blood, so this could be used to predict disease severity.

SARS-CoV-2 and the T cell response

To fight off an infection with SARS-CoV-2, T cells need to be able to identify unique features of the virus called antigens, and scientists have identified a number of these. A high proportion of T cells seem to respond to a specific protein on the virus called a spike protein, meaning that most T cells can react to the virus. This review suggests that vaccines targeting these types of markers on SARS-CoV-2 virus could effectively promote a T cell response and produce antibodies to protect against disease.

The exact strength and type of T cell response in patients with COVID-19 is still unclear. Researchers have found fully functional T cells, more memory T cells, and higher T cell counts in patients with severe disease. Those with mild COVID-19 also had T cells capable of responding well to the virus. T cells that target SARS-CoV-2 and prompt a good immune response have been found in >70% of recovering patients. The specific types of T cells present and the ways in which they respond may be linked to variations in presentation of COVID-19; clinical trials are in place to investigate this.

Disordered immune responses in COVID-19

Respiratory failure is a leading cause of deaths in COVID-19 and is linked to inflammation of the lining of the lungs. A feedback loop in the immune system may lead to this severe inflammation. A cytokine storm is high levels of signalling molecules called cytokines, which promote inflammation in the body. Cytokines are a normal part of the immune response; however, too many of them can cause excessive inflammation and damage. Some researchers are investigating ways of reducing this effect.

Other consequences of COVID-19 include blood clots, cardiovascular problems, liver and kidney damage, and neurological issues, all of which may be linked to disordered T cell responses. T cells can be helpful or harmful depending on the individual’s immune system. Over time they can become ‘exhausted’ and don’t function in the best way to fight off SARS-CoV-2. The virus itself may cause this, however more studies are needed.

Treatments to improve T cell responses in patients with COVID-19

Influencing T cell function is a potential approach to treat COVID-19. This may include developing vaccines that activate T cells specifically, for example using viral proteins or the virus’ genetic material to mimic the presence of the virus.  Additionally, administering cytokines, which play a key role in triggering the immune response within a cell, is a potential option. Other options might include infusing T cells that recognise SARS-CoV-2 to patients that are unwell or stimulating T cells that produce protective cytokines. SARS-CoV-2 also alters the expression of ‘immune checkpoints’, which are molecules that stop the immune system attacking cells at random, so targeting these molecules at an early stage could also be of benefit. An ideal approach could combine targeting immune cells that help regulate the immune response while minimising inflammation.

Finding an antiviral treatment that targets SARS-CoV-2-specific T cells will require a deep understanding of the immune response to the virus, in particular T cells themselves. Many potential therapies are currently in clinical trials.

Toor, S.M., Saleh, R., Sasidharan Nair, V., Taha, R.Z. and Elkord, E. (2021), T‐cell responses and therapies against SARS‐CoV‐2 infection. Immunology, 162: 30-43.

First published 15 September 2020

Summary author Gabriela De Sousa, BSI Research Communications Officer