A year into the COVID-19 pandemic and scientists are making great strides in our understanding of the causative virus, SARS-CoV-2; how it interacts with our body and ways to both treat and prevent infection. With vaccination on the horizon for many of us things are looking up.
The unprecedented scale of global collaboration and data sharing across the scientific community has played no small part in this process. It has resulted in the establishment of a number of expert consortia, specializing in areas such as structural biology and outbreak prediction modeling. One such organization is the Global T cell Expert Consortium (GTEC), an initiative designed to bring together international leading experts in T-cell research.
We spoke to Professor Danny Altmann, GTEC chair and professor of immunology at Imperial College London, about the role that T cells have in viral infections like SARS-CoV-2 and what GTEC is hoping to achieve.
Karen Steward (KS): Many people are aware of the role of antibodies in the development of effective and enduring immunity to viral infections, such as SARS-CoV-2, but much less familiar with the role of T cells in this process. Can you tell us a bit about the part they play and why they are important?
Danny Altmann (DA): For the body to fight off a virus generally requires the “intelligent”, specific, part of your immune system, termed “adaptive immunity.” This involves two type of white blood cell, B cells (which make antibody) and T cells (which make immune effector molecules called cytokines and also kill virus-infected cells) working absolutely in parallel from first encounter with the virus, to expel it from the body. Once the virus has got inside cells, its rather less accessible to antibody attack. At that stage, the T-cell response really comes into its own: its central role is a sophisticated mechanism to recognize those cells in the body that are expressing tiny fragments of processed virus – tiny markers that they’ve become infected. Once recognized, the infected cells are killed.
During early discussions about immunity to COVID-19 there was occasional confusion, with some people seemingly perceiving T cell and B cell immunity as alternative options, along the lines of “it doesn’t matter if you have antibodies to the virus as there are also T cells.” The simple answer is that the two arms largely work together, although they may occasionally become discordant.
KS: Do you think that prior to the COVID-19 pandemic, the importance of T-cell immunity in infectious disease had been underappreciated? How do you think that has impacted previous research focus and decision making and how do you think it is likely to change these in the future?
DA: I’m not sure if it was under-appreciated as such: that is, most medics would always have had a good grasp of the importance of both B and T cells. Think for example about the massive knowledgebase on disease susceptibility in those that lack normal T-cell immunity, for example transplant recipients or those with human immunodeficiency virus (HIV). However, I do think a knowledge gap arises when one considers that most hospital labs would have a very large number of simple, antibody tests on hand, while T-cell tests have been a little more inaccessible, largely the province of research labs. Up to now, the only infectious disease where T-cell testing has played a significant role in diagnosis is in tuberculosis (TB). This is because the high specificity of the T-cell response facilitates assays to pin down the distinction between people who have immunity through BCG vaccination and people who have been infected with the actual mycobacterium. If we only had the will to do it, however, it’s quite hard to think of an infectious disease where we wouldn’t gain significantly greater insights into diagnosis, susceptibility and disease management through wider application of T-cell assays against the microbial pathogen in question.
KS: How have single cell sequencing technologies changed our understanding of T cell and immune system function?
DA: Yes – absolutely magnificently! T cells constitute a whole universe of highly evolved subsets performing differential functions to protect the body. With new technologies we’ve been gaining more insight by the week. Who knew for example that the effector program of a CD4 T cell in the lung might be totally different from one in the liver or in adipose tissue? T-cell immunology has been on an enormous journey over the past 40-years or so. First, we realized they could be resolved into CD4 and CD8 cells, roughly correlating with the functions of cytokine secretion versus killing. Then it gradually came to be appreciated that, once activated by seeing their antigen, T cells can become polarized into highly distinct effector programs, for example the Th1 cells often involved in the response to virus infection, the Th2 cells involved in anti-parasite responses and the Treg cells needed to dampen excessive immunity. With single cell approaches today, we start to define thousands of distinct subsets.
KS: Can you tell us about the aims of GTEC in bringing together global T-cell experts? Why is a consortium like this needed?
DA: I think this is a really exciting prospect. I think, by analogy, of the enormous rewards to biomedical research from the coming together in recent decades of the global genomic sequencing community – new technologies, faster answers, big answers, new directions. I hope that by bringing together T-cell researchers in a similar manner, we can really aim high and accelerate progress to some big answers across many disease processes, whether in infectious disease, cancer, autoimmunity or neurology. As in any other branch of high-tech biomedicine, once you bring good people together and bring new momentum to questions, you simply accelerate the speed at which things happen. For the early years of my career, T-cell analysis was a painstaking, cumbersome business, needing a radioactivity lab where you could handle chromium-51 or tritiated thymidine to label your T cells – I worked in the medical school basement, wearing a lead apron. Since then, we’ve had many advances in terms of cleverer ways of looking at T-cell activation. There’s definitely space to keep thinking of smarter ways to do this, based on our enormous knowledge of T cell biology.
KS: Beyond the COVID-19 pandemic, what do you see as the longer-term role for GTEC in other infectious disease and public health issues?
DA: Well, it will take a long time to be “beyond COVID-19” – that is, I passionately believe we’ll need strong, global programs of antibody and T cell immune monitoring for years to come, monitoring immunity in the population. Otherwise, we’re just sitting ducks waiting for the next debacle. Also, I believe that sorting out the immunopathogenesis of long COVID (“long-haulers”) will need strong molecular immunology, including T-cell analysis. Meanwhile, there will be considerable benefit from the advances across many infectious diseases, cancer, autoimmunity.
Professor Danny Altmann was speaking to Dr Karen Steward, Senior Science Writer for Technology Networks.