Dendritic cells reveal double identity

For nearly three decades, immunologists have believed that specialised sentries in the surface layer of the skin, called Langerhans cells, alert hunter-killer T-cells to seek out and destroy virus-infected cells.

But Melbourne University immunologist Professor Frank Carbone told this week's Lorne Conference on Protein Structure and Function on Phillip Island the dogma requires amendment - Langerhans cells may detect viral infections, but they're not the ultimate bearers of bad tidings to the immune systems.

In a discovery with implications for the development of more efficient vaccines, research groups led by Carbone and Dr Bill Heath, of the Walter and Eliza Hall Medical Research Institute, have shown that there are at least two functionally distinct types of dendritic cells (DCs) that tag-team to rouse the immune system's assassins to action in the case of skin infection.

Session chairman, Nobel laureate immunologist Professor Peter Doherty, had earlier characterised the immune system as a "morass" for researchers mad enough to venture into it. In their expedition into the morass, Carbone, Heath and their colleagues have caught a familiar denizen performing a surprising role.

Carbone said there's no argument that it's Langerhans cells -- the name given to the specialised dendritic cells in the skin -- that initiate the immune response to viruses that infect via the skin.

Langerhans cells were expected to ingest and dissect viral particles with proteolytic enzymes before migrating from the epidermis to the nearest lymph nodes, with the alien peptides 'displayed' atop MHC molecules on their surface. In this way, according to the dogma, the viral antigens are 'presented' to cytotoxic T-cells.

By staining patches of shaved skin on rodents with fluorescent green dye, then experimentally infecting the skin with herpes simplex virus, Carbone and his colleagues observed fluorescent green Langerhans cells migrating from the skin to the lymph nodes.

Naive T-cells wander the body, randomly visiting the lymph nodes to check for dendritic cells bearing foreign antigens.

Carbone said the lymph nodes have a resident population of dendritic cells, identifiable by MHC molecule called CD8. The role of these CD8 dendritic cells has been something of a mystery - until now.

Carbone and colleagues have discovered that the Langerhans cells somehow present the virus antigens to their CD8 cousins, not to the visiting T-cells. It is the CD8 dendritic cells that make the final presentation of foreign antigens to the T-cells, priming them to recognise and destroy infected cells.

Many immunologists believe all dendritic cells are basically the same - but Carbone said these results show that Langerhans cells and, by implication, dendritic cells that populate tissues or organs other than the skin, may also be different to the CD8 cells that populate the lymph nodes. Specifically, they too may deliver, but not present viral antigens to T-cells.

It now seems clear that at least two different types of dendritic cells are involved in relaying foreign antigens to the lymph nodes.

"The ones that do the T-cell priming are different from the ones that detect the infection in the tissues," Carbone said.

"We also find that it doesn't take many Langerhans cells to stimuate a strong and robust immune response. They therefore appear to distribute the antigens through the network, amplifiying the immune response.

"In terms of vaccine development, it takes very little stimulus to get a good response, which suggests that the priming process involves both amplification and prolongation of the signalling process.

"We still don't understand how the immune system deals with infection, and there remain enormous challenges in making vaccines that will induce a cytotoxic T-cell response strong enough to clear chronic infections like HIV, hepatitis C, and malaria.

"If we can understand the interplay between the different types of dendritic cells, it may give us a handle on how to elicit a more robust and thus efficient T-cell response."