Immunology is a complex but vitally important branch of the life sciences. Earlier this year, we attended a Keystone Symposia conference on T cell immunology as media partners. There, we got to speak with Prof. David Masopust, the man who discovered resident memory T cells. His seminal breakthrough opened up a new branch of T cell biology and catapulted the field forwards. Masopust shares his thoughts on the enormous untapped potential of T cells in new treatments and vaccines.
By Amy LeBlanc
David Masopust was only a grad student when he made a discovery that would rewrite the immunology textbooks. Our understanding of the immune system advanced in leaps and bounds throughout the 20th century, but in the early 2000s the prevailing theory was still that T cells only existed in the blood and lymph nodes.
This dogma was turned on its head in 2001, when Masopust discovered resident memory T cells: a different class of T cells that inhabited tissues and organs around the body. Published in Science, his discovery changed the concept of immunological protection against reinfection by revealing memory T-cell populations poised for localized and immediate response. So why did these important immune cells take so long to discover? Masopust explains:
“In the 1990s, we were struggling with a lack of tools capable of visualizing T cells and their antigen specificity. That was hugely problematic, until the first tetramer assay was finally developed in 1996. Armed with this new tool, me and a few other early-career researchers in the lab decided to challenge the dogma. It was really just basic science exploration: deciding not to go with the status quo but to explore further for the sake of curiosity.”
Rewriting the textbooks
Masopust’s findings opened up a whole new branch of T cell biology, vital to understanding localized immunity and immunosurveillance. By lodging in different tissues around the body, resident memory T cells act as sentinels that protect us from reinfection. They accumulate in especially high numbers at the site of the original infection, learning from experience that a breach may be particularly likely there. As this emerging field took shape over the next two decades, the studies that followed have gradually shifted the scientific community’s understanding of immunity as a whole:
I believe we’re on the precipice of a paradigm shift in how we view the immune system: we’re starting to recognize that it has an organism-wide sentinel function that goes far beyond just the pathogens.
“New research has really illustrated that T cells are not just reactionary: they are constantly surveying your body for potential threats. They don’t just respond to an invading pathogen; they are also responsible for maintaining your body’s homeostasis and protecting you from anything that threatens that balance. I believe we’re on the precipice of a paradigm shift in how we view the immune system: we’re starting to recognize that it has an organism-wide sentinel function that goes far beyond just the pathogens.
Immunology is really entering into its golden age. It’s a young field and it’s a hard thing to study. There are multiple cell types, distributed about the entire body. The cells are all communicating with each other using a complex chemical language. It’s complicated, but that’s what makes it fascinating as well. There is still a lot left to learn, and we’re barely scratching the surface in terms of clinical potential.”
Tapping into T cell potential
Further research into memory T cells has helped to generate not only a greater understanding of basic biology, but also a range of clinical advances, particularly in the fight against cancer. When asked about medical treatments that rely on our newfound knowledge of T cell biology, Masopust answered:
“Obviously, immunotherapy has become really big, particularly in oncology. It’s still relatively new, and I think what we’ve seen so far is just the beginning. There is a lot of effort being put into refining existing therapies like checkpoint inhibitors. Treatments in liquid tumors, for example CAR T cell therapies, have also produced some quite frankly amazing results. The next big frontier will be solid tumors, which are a bit more challenging.”
I think a lot of chronic inflammatory diseases will have a range of new therapies available to them as this field develops.
Apart from oncology, Masopust also foresees a lot of potential clinical applications in other widespread diseases:
“We’ve now recognized that resident memory T cell populations drive a lot of autoimmune diseases and allergies, which creates opportunities for treatments through cell depletion or modification. I think a lot of chronic inflammatory diseases will have a range of new therapies available to them as this field develops.”
T cells as vaccines
This year’s coronavirus pandemic has spurred a huge spike in interest for immunological research, especially for new and effective vaccines. According to Masopust, memory T cells may offer new frontiers in vaccine design:
“I think we’re also undergoing a slow shift in vaccinology. In the history of vaccines, we’ve conquered some of the easier pathogens. The low-hanging fruit, if you will. Now, we’re starting to take on some more difficult challenges. Vaccines have entered a new era of sophistication. In the past we’ve used antibodies, which are limited in that they can only see the outside of cells. That is fine if your pathogen always has the same cell surface markers, but if your pathogen has a high mutation rate and the markers change or vary, then it creates a real obstacle because it may render the antibodies ineffective.
T cell protection has the potential to be broader and longer lasting than antibody-based vaccines… I don’t think we have gotten anywhere close to exhausting what is ‘doable’ with T cells.
T cells aren’t limited to outer surface determinants: they see the proteome, which is less variable between for example different strains of influenza. This means T cell protection has the potential to be broader and longer lasting than antibody-based vaccines. That’s their great strength. Their flaw is they don’t see the pathogen until it has already gotten into a cell. So you have to compensate for that by getting enough T cells, in the right locations, to find infected cells quickly before you have too much pathogen amplification. I believe that is achievable. I don’t think we have gotten anywhere close to exhausting what is ‘doable’ with T cells.”
Read this previous BioVox article for more on the long-distance race for a corona vaccine.
Masopust is clearly not only knowledgeable but also very passionate about his research. When asked what he thought was the most exciting thing about studying memory T cells, he answered:
“It’s fun to be part of a field where there is so much left to explore! While we know a lot more now than we did before, T cell research is still in its early days. And there is going to be so much that we can do with the new information we obtain. You’re at the edge of a field where things are just starting to come into focus and major breakthroughs are at your fingertips. It’s great to be a part of that!”
