Bad immune cells can turn good

Scientists from the Garvan Institute of Medical Research have discovered that cells once thought to be useless, and even a liability, could be important tools in the fight against disease — including the development of a vaccine against HIV.

The researchers revealed that the mysterious population of cells in the immune system — which are usually ‘silenced’ because they can harm the body — can provide crucial protection against invading microbes. Their work was carried out in mice and published in the journal Science.

Researchers have known for 30 years that a large number of the immune system’s antibody-producing cells (B cells) were kept silenced. Until now, the cells were thought to be ‘bad apples’ because they each produce an antibody that attacks the body’s own tissues and can cause autoimmune disease.

The discovery of the silenced cells was made 30 years ago by Professor Chris Goodnow, who has been working to understand their function ever since. He asked, “Why does the body keep these cells, whose self-binding antibodies pose a genuine risk to health, instead of destroying them completely as we once thought?”

The new findings appear to answer that question, revealing for the first time that the cells are a crucial part of the body’s immune defences. Far from remaining silent, the cells can be redeemed and reawakened to fight invaders when the body is faced with a disease threat that other immune cells cannot tackle — but only once their ‘bad’ antibodies are made good.

Working with a sophisticated preclinical mouse model, Professor Goodnow and his team showed that the silenced cells can produce antibodies when they encounter an invader that appears highly similar to ‘self’. Crucially, before the cells attack, the antibodies they make are first redeemed through tiny alterations to their DNA sequence. These changes mean that the cells can produce antibodies that no longer threaten the body, but instead become a weapon 5000 times more potent against the invading foreigner.

Because the antibodies in the redeemed cells started out as self-reactive, the improved versions have a powerful ability to recognise ‘almost-self’. They are therefore equipped to attack some of the trickiest microbes that the immune system faces: those that evade detection by disguising themselves to look like normal body tissue, such as Campylobacter and HIV.

“We’ve shown that these silenced cells do have a crucial purpose,” said Dr Deborah Burnett, whose work forms the basis of the study. “Far from ‘clogging up’ the immune system for no good reason, they’re providing weapons to fight off invaders whose ‘wolf in sheep’s clothing’ tactics make it almost impossible for the other cells of the immune system to fight them.”

In the model system tested, only three DNA changes were needed to transform antibodies from dangerous cells to effective weapons against disease: a first change to stop the antibody from binding to ‘self’ and a further two changes to increase their ability to specifically bind the invader.

In experiments conducted at the Australian Synchrotron, the research team showed how the three DNA changes rearrange the tips of the antibody in defined ways, so that it becomes much better at recognising the foreign molecule and worse at recognising ‘self’. In particular, the redeemed antibody fits neatly around a nanoscale ‘dimple’ that is present on the foreign molecule but is absent on self.

Professor Goodnow said the findings will fundamentally change thinking about how the immune system protects us, noting, “We once thought that harmful immune cells were discarded by the body — like a few bad apples in the barrel. Likewise, no-one had any idea that you could start with a ‘bad’ antibody and make it good.

“From these new findings, we now know that every immune cell is precious when it comes to fighting invading microbes — and we’ve learned that the immune system recycles, conserves and polishes up its ‘bad apples’ instead of throwing them away.”

“This research has taken us on an exciting journey,” added Associate Professor Daniel Christ, who co-led the research with Professor Goodnow. “Not only have we uncovered a new kind of immunity, we’ve been able to confirm precisely how a harmful antibody can be transformed into a powerful defender of the body.

“Crucially, the antibodies made by redeemed cells are by no means a fall-back option. In fact, our findings show the opposite — that tweaking ‘bad’ antibodies can make even more powerful antibodies than those developed through established pathways.

“We’re excited about the impact of this new understanding on vaccine development. Our findings indicate that there’s a whole class of B cells out there — the silenced B cells — that might be accessible for vaccine development, and that have so far largely been ignored.”

Image credit: ©stock.adobe.com/au/Sergey Nivens