Scientists unveil a new path towards better immune responses

The immune response can protect us from basically any invader but it can also create disease - like it happens in autoimmunity where it attacks the own body - so to understand its regulation is an important tool to assure its proper functioning.

In an article just published online on the journal Nature Immunology, scientists in Portugal study one of the least understood white blood cells subsets - the gamma delta T cells - and reveal that is composed by two distinct functional groups that can be identified according to the expression of a molecule called CD27, which is also determinant deciding which subset dominates the immune response. The therapeutic potential of the discovery is clear when Julie Ribot, Ana deBarros and Bruno Silva-Santos from the Institute of Molecular Medicine and the Gulbenkian Institute of Science in Lisbon, Portugal show how is possible - by targeting CD27 - to change the immune response, to diminish the numbers of those cells with potential to create toxic autoimmunity.

Gamma delta T cells form a small, unique population of white blood cells that only now starts to be understood. We know they react very quickly- and so seem important orchestrating the first lines of defence - and have a role in the response against infection while also participating in autoimmunity. The contrast between these two possible responses - one healthy and the other pathogenic/toxic - together with their regulatory role highlights how important it is to understand better these cells.

It was with this aim that Bruno Silva-Santos and colleagues decided to look into the presence of CD27 in gamma delta T cells, since this molecule has been found to divide other subsets of white blood cells. And in fact, they found two functional groups according to gamma delta's CD27 expression: cells with CD27 (CD27 positive) that produced the protein INF-gamma, and CD27 negative cells producing IL-17. IFN-gamma and IL-17 are both cytokines - proteins that serve as messengers between cells, crucial in the orchestration of the immune response - and while IFN-gamma mediates the response to infection, IL-17 is a pro-inflammatory cytokine that participates in infection as well, but, in addition, can also lead to chronic inflammation contributing to both autoimmune and allergic responses.

Another observation, and in contrast with what is seen with more classic T cells, was that the two CD27 subsets were very 'fixed/constant' in the cytokines they produced even when activated for the first time. In fact, normally, the immune response - including the cytokines produced by T cells - depends much on the cytokine environment that is around, specially when they are activated for the first time. Instead, gamma delta T cells seemed pre-determined into one of the paths, straight from the beginning, and independently of the environment.  This raised the suspicion that maybe they could be primed very early into their development, even before coming to the periphery where the immune response happens.  A look into the thymus - where all T cells are produced - revealed that, in fact, CD27 positive and negative cells were already associated to their respective cytokine path as early as in the foetal thymus.

Next logical question - since CD27 was present so early - was if this molecule could be involved determining which subset - IFN-gamma or IL-17 producers - developed. This time the researchers looked into mice with no CD27 to find that, in fact, in these mice the gamma delta T cells produced much less IFN-gamma. The role of CD27 pre-determining gamma delta populations was further confirmed when Ribot and colleagues mixed foetal thymus with molecules that bound and activated CD27 and obtained a population with mostly IFN-gamma-producing gamma delta T cells and very few IL17. These experiments showed that, not only CD27 performs a crucial role in the decision of which population emerge during the immune response, but also, and crucially, that this process was possible to be manipulated in laboratory.

Gamma delta T cells are known to respond much quicker - in a mere few hours - in comparison with other T cells subsets, which can take as much as seven days to react when they first find a stimulus. And we know that the initial cytokine production during an infection or pathology is crucial determining which immune response develops, making gamma delta T - and their proper regulation - very important. Bruno Santos-Silva the head of the researchers  says "Since we have pharmacological tools to manipulate CD27 signals, we can envisage "re-educating" these cells, all the way since the thymus, towards one but not the other subset. This may have important clinical repercussions".

A final important point is the fact that recent research shows that IL17 is mainly produced - except in the gut -  by gamma delta T cells and also that this cytokine is linked to more and more cases of chronic inflammation and loss of immune regulation resulting in autoimmunity what makes Ribot, Silva-Santos and colleagues' results particularly pertinent in this moment in time. But Silva-Santos reminds us that "we should note that our work is basic research and was all done in mouse models. We are now studying the human counterparts of these subsets and the first results seem to show that the same happens in human cells but this is still on-going work that needs confirmation."