Immune peacekeepers discovered

How our skin says, “Don’t worry, these are good guys,” revealed today in PNAS.

There are more bacteria living on our skin and in our gut than cells in our body. We need them. But until now no-one knew how the immune system could tell that these bacteria are harmless.

Centenary Institute researchers in Sydney have discovered a set of peacekeepers—immune cells in the outer layers of our skin that stop us from attacking friendly bacteria.

The work will open the way to new therapeutic options for immune-mediated diseases such as inflammatory bowel disease, of which Australia has some of the world’s highest rates.

In a paper published today in the Proceedings of the National Academy of Sciences (PNAS), Professor Barbara Fazekas de St Groth and her team have shown that the immune cells in the outer layer of the skin constantly act as peacekeepers to stop the immune system from reacting the way it normally would. Known as Langerhans cells, they resisted every attempt by the researchers to get them to generate an immune response.

The researchers worked with a group of mice in which only the Langerhans cells could stimulate the immune system. They then activated the Langerhans cells and measured the response.

“No matter what we threw at them to get them to activate a long-term immune response, the Langerhans cells always induced immune tolerance,” Prof Fazekas says.

This result seems to go against the prevailing wisdom in immunology about the workings of dendritic cells, the class of immune cell to which Langerhans cells belong.

Dendritic cells engulf bacteria, viruses or other invaders and put a marker from that invader, known as an antigen, on a protein that can bind to other immune cells.

The antigen reprograms passing T cells, the workhorses of the immune system, which then set off a cascade of responses that eventually lead to the destruction of anything displaying that antigen.

However, the Centenary team (which is affiliated with the University of Sydney and RPA Hospital) found Langerhans cells are very different from other dendritic cells: after turning on the helper T cells, they tell them to self-destruct instead.

“This is the opposite of what you’d usually expect.  In previous studies of immune cells, if there was a flurry of activity, we assumed it was the start of a long-term immune response,” Prof Fazekas says.

However, the immune system is a layered defence­—the next layer of skin has different kinds of dendritic cells, which program on-going responses against bacteria. So if bacteria penetrate deep enough to meet these cells, the immune response will kill them.

In inflammatory bowel disease, which afflicts thousands of Australians, the immune system is activated against the gut bacteria, which are usually left alone.

This discovery opens up possible ways to figure out why this disorder occurs and to find treatments to a range of diseases of the immune system.

“There is so much we don’t know about the immune system, but sometimes just mimicking what the system does, like we do with vaccines, can work very well” Prof Fazekas says,

“If we do manage to mimic what Langerhans cells do, then we could develop treatments that would precisely tolerise against specific antigens – just like the immune system of the skin does now.”

Centenary Institute executive director Professor Mathew Vadas says this latest paper comes just weeks after Centenary researcher Patrick Bertolino made the front cover of PNAS for his paper on immune response in the liver.

“The Centenary Institute is interested in understanding how the immune system works—these discoveries and others already in the pipeline here are a major step forward towards that goal,” Prof Vadas says.

• For interviews contact: Barbara Fazekas de St Groth:+61 2 9565 6137
• For hi-res images, backgrounder, paper and full release go to: http://www.scienceinpublic.com.au/centenary
• or call Andrew Wight on (03) 9398 1416, +61 422 982 829

An antigen is a substance or molecule that when introduced into the body usually triggers the immune system, which then kills or neutralizes any antigen-presenting cell. The antigen, which could be made by a bacterium, marks it as a foreign and potentially harmful invader.

T cells are white blood cells that form a key part of the immune system.  They are produced in an organ called the thymus and then move out to the blood, spleen and lymph nodes. For T cells to see foreign antigen, it has to first be taken up by dendritic cells and displayed on their surface. The dendritic cells also send a signal that activates the T cells to reproduce themselves and to turn on functions that recruit many other cells into the immune response.

What is inflammatory bowel disease?

Inflammatory bowel disease (IBD) is a group of inflammatory conditions of the large and small intestines. The major types of IBD are Crohn’s disease and ulcerative colitis.  The causes of these diseases are abnormal immune responses where the immune system is thought to activate against harmless bacteria within the bowel.  It is also believed there is some genetic component, but the mechanism of these diseases is still poorly understood.

Citation

PNAS subscribers can find the full paper here.

Langerhans cells are pre-committed to immune tolerance induction

Elena Shklovskayaa, Brendan J. O’Sullivanb, Lai Guan Ngc,d,e, Ben Roedigera,c,

Ranjeny Thomasb, Wolfgang Weningerc,d and Barbara Fazekas de St Grotha,d

a T Cell Biology Research Program, Centenary Institute of Cancer Medicine and Cell

Biology, Locked Bag #6, NSW 2042, Australia

b Diamantina Institute for Cancer, Immunology, and Metabolic Medicine, University

of Queensland, Level 4, R-wing, Building 1, Princess Alexandra Hospital, Brisbane,

QLD 4102, Australia.

c Immune Imaging Program, Centenary Institute of Cancer Medicine and Cell

Biology, Locked Bag #6, Newtown, NSW 2042, Australia

d Discipline of Dermatology, University of Sydney, NSW 2006, Australia

e Present address: Singapore Immunology Network (SIgN), Agency for Science,

Technology and Research (A*STAR), Biopolis, Singapore

Abstract

Antigen-dependent interactions between T lymphocytes and dendritic cells (DCs) can produce two distinct outcomes: tolerance and immunity.

It is generally considered that all DC subsets are capable of supporting both tolerogenic and immunogenic responses, depending on their exposure to activating signals.

Here we tested whether epidermal Langerhans cells (LCs) can support immunogenic responses in vivo in the absence of antigen presentation by other DC subsets.

CD4 T cells responding to antigen presentation by activated LCs initially proliferated but then failed to differentiate into effector/memory cells or to survive long-term.

The tolerogenic function of LCs was maintained after exposure to potent adjuvants and occurred despite upregulation of the co-stimulatory molecules CD80, CD86 and IL-12, but was consistent with their failure to translocate the NF-κB family member RelB from the cytoplasm to the nucleus.

Commitment of LCs to tolerogenic function may explain why commensal micro-organisms expressing TLR ligands but confined to the skin epithelium are tolerated, while invading pathogens that breach the epithelial basement membrane and activate DDCs stimulate a strong immune response.

About Barbara Fazekas de St Groth:

Professor Barbara Fazekas de St Groth is an immunologist who heads a research group at the Centenary Institute in Sydney. Her work is aimed at understanding how the immune system is regulated.  She is an authority on the “hygiene hypothesis” and the suspected role of our hygiene habits in the prevalence diseases caused by inappropriate immune responses.

About the Centenary Institute:

Centenary Institute’s dedicated scientists conduct fundamental research to understand the work of the body’s genes, cells and proteins.  Centenary’s affiliation with 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.

More at: http://www.centenary.org.au/

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