How our liver kills “killer cells”

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Our livers can fight back against the immune system – reducing organ rejection but also making us more susceptible to liver disease.

Scientists at the Centenary Institute in Sydney have seen for the first time (in mice) how the liver goes independent, engulfing and destroying the body’s defence troops — T-cells.

Their discovery, published overnight in PNAS (Proceedings of the National Academy of Sciences), opens the way to both new approaches to transplant rejection, and to the fight against hepatitis and other chronic liver diseases which affect over 200,000 Australians and hundreds of millions of people worldwide.

“In 2004, we discovered that healthy liver cells can engulf active immune cells, known as T-cells—and now we’ve seen that those T-cells are actually destroyed.” says Dr Patrick Bertolino, the leader of the research team at the Centenary Institute.

“The liver is an amazing organ,” Dr Bertolino says. “Most people think it just breaks down alcohol, but it’s the factory of the body – breaking down substances we don’t want and making the ones that we do.

“We now know liver cells also have the ability to subvert the orders of the immune system,” he says, “Our discovery might explain why liver transplants have lower rejection rates than other organ transplants.”

“When Patrick first told me he had evidence T-cells might be eaten by liver cells, showing a possible link to the liver’s ability to dial down the immune response, I thought the idea was crazy,” says lead author Volker Benseler. But Volker accepted Patrick’s challenge to prove it and went on to find healthy mouse liver cells eating T-cells, which was unexpected as this ‘cell cannibalism’ had only previously been seen in tumour cells.

One potential benefit of the research is reducing rejection in organ transplants. About 200 liver transplants are performed in Australia each year and up to 25 per cent of cases end in rejection.

In transplantation, the new organ is seen by the body as a foreign object: the spleen or lymph nodes tell naïve T-cells to replicate and turn into killer T-cells, which are sent off to invade and kill the ‘foreign’ cells.

What the researchers have discovered is the liver goes around this process: liver cells signal to naïve T-cells and digest them before they have a chance to become killer T-cells.

Centenary Institute’s Liver Unit leader, Professor Geoff McCaughan, says the cocktail of immunosuppressive drugs that organ transplant patients receive reduce the odds of organ rejection but makes patients’ immune systems weak, leaving them open to serious infection from otherwise minor illnesses like cold or flu. These drugs also predispose the patient to long term heart disease and cancer. “If we can harness the way the liver controls T-cells, then long-term there is a chance that transplant patients won’t need these drugs,” he says.

Another spin-off of this latest work could be to find a way to dial down the liver’s destruction of T-cells, increasing the liver’s defence against infections like hepatitis.

In Australia, 217,000 people are living with chronic hepatitis C and it is estimated that 170 million people worldwide are infected with hepatitis C, for which there is no vaccine.

Exploiting signalling pathways between the liver and the T-cells is one possible outcome of this discovery, but first the molecular biology that underpins those pathways will need to be worked out.

“It could be another ten years plus before we see drugs derived from this work enter clinical trials,” Dr Bertolino says.

However, the research opens up a new question – why? “We don’t yet know why the liver has developed this ability,” says Dr Bertolino. “The discovery reminds us that we still have a lot to learn about the liver.”

• Further information call Andrew Wight on (03) 9398 1416, 0422 982 829
• For interviews contact: Andrew Wight to arrange an interview with Patrick Bertolino.

What is the liver?

The liver is a large organ that causes important changes in many of the substances contained in blood passing passes through it, like breaking down alcohol, converting sugars into glycogen or forming urea. In humans it is the largest gland in the body, weighs about 1.1 kilograms, is dark red, and occupies the upper right portion of the abdominal cavity immediately below the diaphragm.

Has this cell-eating behaviour been seen in human livers?

Not yet. The study saw this in mice, but the same mechanism is thought to occur in our bodies as mice and humans share the ability to decrease levels of killer T-cells in the liver.

Is this behaviour found in other organs?

No, liver cells are the only organ cells that appear to have this ability. Transplants from the same donor done at the same time as a liver transplant have better rates of successfully grafting, but the mechanism for this is poorly understood.

How far away are applications in routine therapy?

At least 10 years. The basic science of this discovery opens up new gateways for research: exploiting signalling pathways between the liver and the T-cells is one example, but these pathways are poorly understood at present.

What are T-cells and killer T-cells?

T-cells are the cells that make up a key part of the immune system. They are produced in an organ called the thymus and when foreign or abnormal molecules are detected, the spleen or lymph nodes send a signal activating naïve T-cells to turn some of them into killer T-cells and to make many copies.

Killer T-cells recognise small fragments of virus or other foreign material peeking out from the cell membrane and launch an attack to kill the infected cell. Higher numbers of these cells mean a higher immune response.

About liver transplants:

Australia-wide 200 people receive liver transplants each year.

Cost of a transplant: First-year charge: about AUD$150,000. Annual follow-up charge: AUD$10,000-20,000

What’s the rejection rate for liver transplants?

About 10- 15 per cent of liver transplant operations end in rejection of the new organ.

Other organs don’t have the ability to dial down the immune response, so without immunosuppressant drugs they would almost certainly be rejected.

What are immunosuppressive drugs?

They are drugs that act to depress the immune system. They are used following organ transplants to decrease the body’s ability to reject the donor organ. Patients must stay on immunosuppressive drugs following the operation to continually fight rejection. The downside is that the body can no longer defend against even ordinarily harmless cold and flu viruses. Drug examples include Ciclosporin and Tacrolimus.

Dr Patrick Bertolino

Dr Patrick Bertolino is the principal author of the PNAS paper and leader of the liver immunology team at Centenary.

Dr Patrick Bertolino received his PhD in 1992 from the University of Lyon in France. He then undertook two postdoctoral studies at the Walter and Eliza Hall Institute in Melbourne, Australia (1992-95) and ENS-Lyon in France (1995-97) before settling in at the Centenary Institute.

Dr Bertolino is an expert in liver immunology and has made major contributions relating to the ability of the liver to induce tolerance in transplantation, and chronic HCV infection.

Centenary Institute

Centenary Institute’s dedicated scientists conduct fundamental research to understand the work of the body’s genes, cells and proteins. Centenary’s connection to the RPA Hospital and the University of Sydney means they can translate directly the discoveries in the lab to prevent diseases that affect so many of us.

Hepatocyte entry leads to degradation of autoreactive CD8 T cells

Volker Benseler,1,3 Alessandra Warren,2 Michelle Vo,1 Lauren E. Holz,1 Szun Szun Tay,1 David

LeCouteur,2 Eamon Breen,1 Anthony Allison,4 Nico van Rooijen,5 Claire McGuffog,1 Hans-

Jürgen Schlitt, 3 David G. Bowen,1 Geoffrey W. McCaughan,1 Patrick Bertolino1

Although most self-reactive T cells are eliminated in the thymus, mechanisms to inactivate or control T cells specific for extrathymic antigens are required and exist in the periphery. By investigating the site in which autoreactive T cells are tolerized, we identify a novel mechanism of peripheral deletion in which naïve autoreactive CD8 T cells are rapidly eliminated in the liver following intrahepatic activation. T cells actively invade hepatocytes, enter endosomal/lysosomal compartments, and are degraded. Blockade of this process leads to accumulation of autoreactive CD8 T cells in the liver and breach of tolerance, with the development of autoimmune hepatitis. Cell into cell invasion, or emperipolesis, is a long-observed phenomenon for which a physiological role has not been previously demonstrated. We propose that this “suicidal emperipolesis” is a novel mechanism of autoreactive T cell deletion, a process critical for the maintenance of tolerance.

1. Centenary Institute and AW Morrow Gastroenterology and Liver Centre, Royal Price Alfred Hospital and University of Sydney, Sydney, Australia

2. CERA and ANZAC Research Institute, Concord RG Hospital and University of Sydney, Sydney, Australia

3. Department of Surgery, University of Regensburg, Regensburg, Germany

4. Alavita Inc., Mountain View, California, USA

5. Vrije Univeriteit, VUMC, Department of Molecular Cell Biology, Faculty of Medicine, Amsterdam, Netherlands

 

Full copies of the paper available to working press, contact Andrew Wight on (03) 9398 1416, 0422 982 829