Immune pathologies

The second focus of Strasser's presentation is another TNF-related protein involved in mediating tissue pathology when immune responses are highly activated, called Fas-ligand (FasL). It has one dedicated receptor called Fas, whose activation in any cell type can trigger cell death.

"The FasL/Fas system is critical for deletion of chronically activated (foreign antigen or auto-antigen specific) T and B cells," he says. "Accordingly, mutations in Fas or FasL result in immune pathologies."

However, what regulates FasL post-translationally was unknown. This ligand is synthesised mainly by T lymphocytes, but not transported immediately to the cell surface.

Instead, it is stored in cytolytic granules or vesicles inside the cells, thereby introducing another level of control on the molecule. Upon antigenic activation of the T cells, these intracellular storage compartments fuse with the plasma membrane, placing Fas ligand on the surface where it can be presented to the environment in a highly aggregated form.

FasL on the cell surface can be cleaved by extracellular proteases thereby producing a soluble (trimeric) form.

The controversial issue in the field prior to Strasser's work was which form of FasL is bioactive - is the membrane-bound form used to kill target cells or is it the secreted, cleaved form?

"Half of the world believed one theory and half believed the other," Strasser says.

In addition, some in the field also believed that the secreted form of the ligand does not kill cells, but instead has a separate function to inactivate target cells.

Strasser decided to address all these questions using his group's substantial mutational engineering expertise in mice - making subtle mutations in the endogenous Fas-ligand genes. They made knock-in mice in which Fas ligand could either only be secreted or only be membrane-bound.

"We thought that by putting these animals through their paces we should be able to answer all of the questions on this that are out there ... and we were right. We also found a few entirely surprising things, which was nice."

Strasser's experiments showed that the membrane-bound form of Fas-ligand is solely responsible for initiating cell death in the target cells, and that the secreted form has no such function.

"It also became clear that the cleaved and secreted Fas ligand has a function that we had not been thinking about, so this other group of people were also right.

"All of the mice that only make secreted Fas ligand eventually develop a range of defects and diseases that the animals not able to cleave and release Fas ligand and even animals that completely lack the function of Fas ligand never get - cancer, heart pathology, autoimmune problems, severe dermatitis and so on. What the nature of this activation is, however, we do not know."

Together, these results suggested that membrane-bound Fas ligand guards against autoimmunity, while secreted Fas ligand may play a critical role in tissue damage and tumour suppression.

While striving towards a complete understanding of the interplay between apoptosis and the immune system, Strasser's findings along the way continue to significantly inform the field.

"Beyond the basic research, we always have a bit of a wondering eye on whether anything we see in the mice is relevant to a disease setting, in collaboration with clinicians and other scientists," he says.

"It turns out that a lot of treatments used in cancer therapy also work extremely well for some autoimmune diseases, most likely because both diseases involve defects in apoptosis as an underlying cause. So if you have a drug that reinstates normal apoptosis you can potentially treat either of those disease families.

"A recent example of this is the anti-CD20 antibody reagents (Rituximab) developed by Genentech for the treatment of certain types of B-cell lymphoma - they also work extremely well for treating rheumatoid arthritis."