The autoimmune disorder psoriasis inflicts itchy, red patches of thickened skin on more than 100 million people worldwide. Immune cells gone awry in some way direct skin cells to proliferate to form these lesions. Immunologist Yan Zheng and his colleagues at the biotechnology company Genentech in San Francisco, California, wanted to find which wires had got crossed between the immune system and the skin cells. They had several bits of key information, but like a frustrating jigsaw puzzle, it was impossible to fit them together to form a complete picture.

“Psoriasis is characterized by a lot of white blood cells infiltrating into the skin, and by thickening of the epidermis,” Zheng explains. These white blood cells include T cells, which are known to be important in the disease. Patients also have raised levels of certain cytokines, proteins that act as communication signals between cells and which are produced by T cells, among others. One of these cytokines, interleukin 22 (IL-22), caught the group's attention, as its receptor is present on skin cells.

Were the infiltrating T cells the source of this IL-22? And if so, was it the cause of skin cell proliferation? “We wanted to ask 'what's the source of IL-22 and what's the target?',” says Zheng. The researchers knew that IL-22 could be produced by T cells, but they needed to find out which particular subset.

They started by testing TH1 cells, the most likely candidates, but Zheng and group leader Wenjun Ouyang were not convinced by the small amounts of IL-22 these cells produced. Around this time, other researchers identified a new subset of T cells, called TH17. The Genentech team immediately set up tests of these cells and showed that they could indeed pump out large quantities of IL-22 (see page 648).

This was only the start. “If we wanted to prove that IL-22 is truly a link between T cells and psoriasis, we had to try to pick an in vivo model to show it,” says Zheng. There is no proper animal model of psoriasis, so Zheng and Ouyang scoured the literature looking for the best approximation.

They knew that psoriasis patients also had raised levels of the pro-inflammatory cytokine IL-23, and that some patients had responded well to an antibody treatment that blocks IL-23. What's more, Zheng had shown that adding IL-23 to the TH17 cells in the lab dish made them produce IL-22.

The team found previous work in which injection of IL-23 into mouse ears caused the ear skin to thicken. This model brought all the parts together. Using it, Zheng and his colleagues could show that the IL-23 induced T cells in the ears, possibly TH17 cells, to produce IL-22. And almost no skin thickening occurred in a mouse that lacked the gene for IL-22. This clearly marked IL-22 as the missing signal between the invading T cells and the skin cells' overgrowth.

“Once we picked the animal model, everything started to make sense,” says Zheng. “It only took six months to finish the project.” Ouyang's group was the first to the finish line in competition with several other labs to establish the nature of the link between T cells, cytokines and psoriasis. The next task is to find the trigger that causes the release of IL-23 in the first place.