How severe viral infections overwhelm immune cells

When it comes to fighting viruses and cancers, our bodies rely on a type of white blood cell called Killer T cells that recognise and eliminate infected cells, effectively stopping the infection or tumour from progressing.

While T cells are tremendously efficient infection fighters; they can’t keep fighting forever. So at some point they effectively turn off in a process termed ‘immune exhaustion’. This involves the cells expressing high levels of so-called immune ‘checkpoints’, including a receptor called PD-1, which limit the further activation of T cells.

This is a major problem in those cases where a virus evades our immune system and persists over a long time. It can result in chronic infections like those caused by the Human immunodeficiency virus (HIV) or hepatitis viruses. Immune exhaustion is also a common feature in cancer, leaving tumours to grow unchecked.

Cancer therapy over the last decade has been revolutionised by drugs that can block immune checkpoints and thereby reactivate the patient’s own immune response. However, while many patients experience durable benefits from these drugs, others don’t respond.

We and our colleagues have recently identified a new population of T cells that can be targeted to keep the immune response going for longer. We have discovered that T cell responses to chronic infections and cancers are maintained by a specialised population of T cells with self-renewing capacity – so called precursor T cells.

These cells not only ensure continuous T cell immunity, they are also the reason why checkpoint inhibitor drugs work.

We also found that immune exhaustion can happen in response to an overwhelming infection, not just a chronic one as widely believed. This means targeting precursor T cells may eventually lead to therapies for treating severe infections like COVID-19.

In our study, published in Nature Immunology, we dissected the pathways that lead to the generation of precursor cells during viral infection. For this, we compared the initial phase of T cell responses to a mild and an overwhelming infection.

Strikingly, when the immune system was exposed to large amounts of virus, T cells showed signs of exhaustion within the first few days of infection. This is in stark contrast to the current dominant thinking that exhaustion develops progressively over time due to persistent or chronic exposure.

While an overwhelming viral infection resulted in early immune exhaustion, we also found that it induced the generation of large numbers of precursor cells.

To gain mechanistic insight into the pathways that lead to T cell exhaustion and precursor cell generation, we performed genome wide profiling and discovered that T cells responding to overwhelming infections undergo substantial changes not only in their gene expression but also in their epigenetics.

This means that initial exposure to large amounts of virus can affect gene expression in T cells in the long run even when the virus has disappeared.

Our findings are exciting as they provide new insights into the underlying causes of immune exhaustion and the mechanisms that can counteract it. This knowledge can be used to devise new strategies in cancer therapy or the development of new approaches for the treatment of severe or chronic viral infections.

Specifically, our data suggest that the frequencies and function of precursor T cells could be used as an early predictor for the quality of someone’s immune response to an infection or cancer.

They also imply that early intervention using drugs that interfere with immune exhaustion could extend the immune response, making it more effective.

As we alluded to earlier, the results are of particular interest in light of COVID-19. The exact mechanisms of the immune response to SARS-COV2, the virus that causes COVID-19, are still the subject of intense research; however, it is clear that T cells play an important role.

Strikingly, although COVID-19 is caused by an acute rather than a chronic infection, T cells in patients with severe disease show signs of exhaustion. Our research provides an explanation for these observations as we demonstrate that T cell exhaustion occurs within the first few days of a severe infection.

It means that drugs that can modulate T cell exhaustion may be one way of improving immunity to SARS-COV2.

However, interfering with T cell exhaustion may come at a cost. It is important to understand that T cell exhaustion has primarily evolved as a protective mechanism. Indeed, chronic viral infections have been with mammals, including humans, throughout evolution.

If T cells vigorously fight a persistent virus over extended periods, the unchecked inflammation would result in significant collateral tissue damage.

By limiting T cell functionality through exhaustion, a truce is established in our bodies and immune-related tissue destruction is prevented. Otherwise, high virus loads might elicit very strong immune responses that may cause more harm than good.

It means that any therapeutic approaches that interfere with immune exhaustion by targeting precursor T cells will need to be carefully evaluated against the risk of unintended side effects caused by an unrestrained T cell response. However, precursor T cells may well be the most promising target of immunotherapy in both infection and cancer.

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