Viruses, such as those that cause the common cold or flu, are a particularly devious form of intruder to tackle. Once they enter their host, these infectious agents find cells to hide in while they reproduce in order to infiltrate more targets. Fortunately for us our internal defence system has a trick up its sleeve to seek out this hidden threat. It recruits a specialized form of white blood cell, T killer lymphocytes, that can identify and destroy virus-infected cells, and yet can somehow leave normal healthy cells unharmed.

Investigating how this form of virus scan works turned out to provide profound insights into how the immune system functions at the cellular level, and it is for these achievements that Peter Doherty and Rolf Zinkernagel received the 1996 Nobel Prize in Physiology or Medicine. Investigating how mice are protected against infection from a viral agent that can cause the disease meningitis, they were surprised to find that virus-killing T lymphocytes taken from a mouse could only execute their destructive effect in infected cells belonging to the same strain. Doherty and Zinkernagel proposed that lymphocytes ignored infected cells in other strains because they need to simultaneously recognise two distinct signals on their suspected target – a specific molecule belonging to the concealed virus, and a specific protein marker found on all host cells that signifies that it belongs to itself. Closer inspection revealed that the virus’ molecule actually distorts the host’s marker protein by attaching to it, and this altered self protein informs the T lymphocytes that the cell is infected.

Doherty and Zinkernagel’s findings finally unmasked the true purpose of these self-recognition protein molecules, the major histocompatibility antigens. As early as the 1940s, researchers investigating adverse effects in organ transplants had pointed out that the body rejects foreign, incompatible tissues by recognizing that they carry different versions of the major histocompatibility antigens from their own. Why these proteins create a barrier to transplantation was far from obvious, but the discoveries of Doherty and Zinkernagel revealed that this is merely an unavoidable side-effect of their true biological function. Acting as a surveillance system to distinguish self from non-self, these major histocompatibility antigens allow immune cells to make their crucial life-or-death decision in the face of numerous threats.