Winning an Oscar in immunology

Have you ever wondered what it is that scientists get so excited about? Ana de Barros from the Instituto de Medicina Molecular in Lisbon, Portugal, shares with us the excitement of researching the immune system.

T cells are generally considered part of the adaptive immune response, because they not only eliminate an invader (and the cells it has invaded), but also produce memory cells. As their name implies, these memory cells ‘remember’ that invader for as long as the animal lives, so this immune response adapts very quickly: if that same invader strikes again, the memory cells will recognise and destroy it. This adaptive immune response, which only vertebrates possess, is activated by the innate immune response, the non-specific defence system found in all classes of animal and plant life.

The innate immune response is the first line of defence: the initial reaction to (and attempted elimination of) invaders. Unlike the adaptive immune response, the innate immune response does not confer long-lasting or protective immunity, but it is a swifter and more general response.

We found that our suspicions were well founded: CD27 can be used to identify a particular subtype of γδ T cell. But what was most interesting was that we discovered that the presence of this protein doesn’t merely characterise this subtype of γδ T cell, it actually drives its formation. Within the thymus, the precursors of γδ T cells that mature in the presence of CD27 (CD27+) produce a cytokine called interferon-gamma (IFNγ), whereas cells that mature without CD27 (CD27-) produce primarily a different cytokine, interleukin-17 (IL-17). The presence or absence of the cytokine CD27 thus defines which subtype a gd T cell will belong to (see top diagram below).

γδ T cells play an important role in initiating a quick immune response to various parasites, including the malaria parasite Plasmodium. In humans, this parasite multiplies in the liver, and then spreads to the blood stream, infecting red blood cells, which it destroys. In severe cases this can clog the blood vessels that carry blood to the brain, causing what is known as cerebral malaria. We were interested in discovering whether the different subtypes of γδ T cells influenced this outcome differently: was one subtype of γδ T cell better at preventing cerebral malaria than the other?

To analyse the behaviour of both gd subtypes in the course of infection, we used mice infected with a strain of Plasmodium as a model for what happens in humans. We compared two groups of mice: one group with CD27 in most of their cells (so the majority of their cells produced IFNg), and another genetically engineered group in which none of the maturing γδ T cells had CD27 – which meant that they produced less IFNγ. Both groups of mice were infected with the malaria parasite, and we found that CD27 does indeed seem to influence the development of cerebral malaria.

In short, we were the first to describe a function for CD27 in T-cell precursors in the thymus – and the fact that Nature Immunology decided to publish our article is recognition of just how important these findings are. As our group leader, Bruno Silva-Santos, explains, “We are now investigating the analogous processes in human cells. Our long-term goal is to… be able to manipulate [γδ T cells] for therapeutic purposes such as fighting autoimmune diseases and cancer.”