Nobel Prize for Medicine: Winners identified ‘security guards of immune system’, significant for cancer, autoimmune disease treatment

How does the immune system fight viruses, bacteria and microbes without damaging the body’s own cells?

This question had long perplexed researchers studying the immune system. By the 1980s, researchers had recognised central tolerance, a process by which T cells that recognise the body’s own proteins are eliminated. T cells are a type of white blood cell that helps the body effectively fight off infections.

As things turned out, the immune system is more complex. Although the presence of a special type of T cell which prevents other T cells from attacking the body was previously hypothesised, this theory was abandoned after some researchers presented false evidence and far-fetched conclusions.

Sakaguchi swam against the tide, and in a 1995 paper presented evidence for a new type of T cell “police” that essentially keeps other T cells from attacking the body’s own cells. This new class was called regulatory T cells, and the process by which it protected the body came to be known as peripheral tolerance.

The experiments

Sakaguchi surgically removed the thymus — the organ where T cells mature — in newborn mice. His hypothesis was that this would result in the mice developing fewer T cells, and having a weaker immune system. But when this surgery took place three days after the mice were born, they developed autoimmune diseases, with their immune system going into an overdrive.

To understand what was happening, Sakaguchi injected T cells isolated from genetically identical healthy mice into those without the thymus. These mice did not develop autoimmune conditions. This convinced Sakaguchi of the presence of the T cell “police”. He published his results a decade later, after figuring out how to detect these cells.

However, researchers in the field remained unconvinced. Enter Mary Brunkow and Fred Ramsdell. In their search for therapies for autoimmune diseases, they became interested in the scurfy mice: ones with scaley, flaky skin that live only for a few weeks. Researchers in the 1990s had discovered that the T cells in the scurfy mice were attacking and destroying their tissues, but no one knew what the mutant gene was.

Brunkow and Ramsdell, who worked at the biotech company Celltech Chiroscience, decided to look for this needle in a haystack. They narrowed their search down to 500,000 nucleotides in the mouse DNA, and after mapping these, they identified 20 genes that were likely to be causing this autoimmune condition in the mice.

In 2001, they revealed that the FOXP3 gene was responsible for autoimmunity in the scurfy mice as well as the human disease IPEX.

And, within two years, this finding allowed Sakaguchi to prove that the FOXP3 gene controls the development of regulatory T cells.

The significance

Once the function of these new T cells were known, researchers realised that some tumours can attract a large number of these regulatory T cells, thereby protecting it from the other T cells.

“When a cancerous tumour has a lot of regulatory T cells, they can prevent other T cells from killing the cancerous cells. This is one of the obstacles that Car-T cell therapy — therapies where a person’s own immune cells are modified to better fight the cancer cells — tries to overcome. This is also one of the mechanisms of action for many new cancer immunotherapies, which work by reducing the action of the regulatory T cells to ensure that the treatments are more effective,” said Dr Hasmukh Jain, a specialist of blood cancers from Tata Memorial Hospital.

He says that these therapies can at times lead to autoimmune conditions or the immune system going into overdrive as well.

There are also clinical trials underway to test therapies that can promote formation of more regulatory T cells in patients with autoimmune conditions. They are looking at whether this can prevent the rejection of organs after transplant. Similar to Car-T therapy for cancers, researchers are looking at modifying these T cells in a laboratory and giving them to patients to calm an overactive immune system.