Researchers from McGill University and the US National Cancer Institute (NCI) have made surprising discoveries about our immune system. Using mathematical modeling to look at specific aspects of immune responses in mice and humans, their data-driven approach, described in a recent article in Science, reveals that immune responses may exist on a finer spectrum than previously thought. The results also suggest that messengers are key in the battle between the body’s defenses and intruders. These findings could enhance cancer and other immunotherapies.
Fever, cough and sore throat – symptoms that have come into the limelight in the era of COVID-19 – are just some of the telltale signs of the body’s immune system starting to work against an unwanted intruder. Whether caused by an infection, an allergen, or a vaccine, immune responses are driven by a complex set of cellular processes that can persist over several days or even weeks.
Much is known about the systemic processes that play a role in immune responses. But due to the huge number of variables involved, deciding what to focus on to develop treatments or vaccines proves to be a lot like researching A needle in a haystack. That may now change thanks to a new study by researchers from McGill University and the US National Cancer Institute (NCI), recently published in Sciences.
Focus on a key process in the immune system: the role of proteins called cytokines in sending the body’s signals and responses.
The decisive role of the messengers
Our immune system is often described as a battle. Some critical white blood cells (called T cells) travel through the bloodstream, lymphatic system, and into tissues, looking for traces of microorganisms and other invaders known as antigens. To avoid attacking healthy cells indiscriminately, T cells propagate until they recognize a specific antigen; Only then do they send messengers in the form of cytokines to activate an alert system and signal that all is not well.
“You might think that there are many very different parameters in the immune response that are critical — for example, it might vary the number of T cells that are produced to fight off invaders, or the number of invaders (antigens) themselves,” Paul explains. François, a McGill biophysicist who led the data analysis team, which included McGill physics doctoral students François Bourassa and Thomas Rademaker. “But the big surprise is, in fact, that what really matters is the strength of the antigen.”
Solving numbers helps determine the basics
Until now, it has been difficult to measure antigen strength – seen in how effective an antigen is in stimulating T cells to respond – independently of the amount of antigen present in any given experiment.
But using a data-driven approach, and thanks to a critical collaboration with the National Cancer Institute, François and colleagues were able to decode the highly variable phenomenon of cytokine production to give a reliable reading of antigen strength. This is potentially very useful for predicting how well a vaccine candidate or immunotherapy drug will work.
To study this phenomenon in detail, National Cancer Institute researchers, led by Gregoire Altan Bonnet, have developed an automated platform to conduct dozens of experiments simultaneously, exposing T cells to various antigens and conditions. Siraj Ashar, a graduate student in the Altan-Bonnet lab, has optimized the automated system in order to collect massive amounts of data in a fraction of the time it would have taken to perform the same experiments manually.
Altan Punnett noted that, “Assembling a comprehensive map of the dynamics of T-cell-generated cytokines in highly diverse environments presents a challenge and an opportunity to better understand how T cells ‘view the world of antigens and coordinate immune responses’.”
McGill members on the team then used machine learning to process the data generated from those experiments, and mathematical models to capture meaningful patterns in the data. This data-driven modeling revealed surprisingly simple rules at the heart of what might appear to be an extremely complex process subject to multiple variables.
The spectrum of immune reactions?
The analysis also showed that patterns of cytokine release carried information about the type of antigen encountered and characterized six distinct cellular responses rather than the three typically recognized.
“This supports the idea that immune responses exist along a spectrum rather than as a binary on and off switch,” adds Francois. “There may be different levels of the immune response that can be tuned to the right level of alert depending on the complexity of the situation.”
This new understanding is likely to advance strategies for immunotherapies that rely on T cells engineered to target a patient’s tumors.