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Hi. Thanks for coming to listen to our talks today. My name is Susan Kaech and I’m director of the NOMIS Center for Immunobiology and Microbial Pathogenesis at the Salk Institute, and I wanted to talk to you today about something that’s very relevant, very forefront to our lives, which is how does our immune system remember? How does our immune system develop long-lived immunity to pathogens that infect us and cause obviously severe illness and death, as what we’re facing today with the COVID-19 pandemic.
This is a photo that you might remember yourself personally, having been vaccinated with polio in the day that the polio vaccine was declared safe and effective became something celebrated and revered across the globe because it meant that children would be saved and people would be saved from this devastating illness. Now being at the Salk Institute, which was founded essentially on the basis of the principle of long-term immunity, and normally we would be sitting in the Salk auditorium for the Carta symposia, it reminds us and is cemented in some ways, if you will, in our understanding the foundations of how our immune system operates. And what I want to talk to you about today is the basis of vaccination, why it works, and how does our immune system develop this long-lived immunity to remember pathogens that we’ve experienced prior.
Now, all living organisms have some form of immunity and immune defense. In our particular, and these immune systems, these immune responses, this form of immunity is shaped on fundamental traits, cardinal traits. Now, every animal has the ability to recognize and sense pathogens in the environment and to incorporate that diversity of the different types of pathogens that the animal can sense, and plants of course as well, can sense this, there’s this diversity must be immense, to have the ability to sense and recognize numerous and many different types of pathogens in our environment.
And so this diversity is one of the most, is what we call the cardinal traits, but specificity is also essential. And that ability to recognize the pathogen from self, the self, non-self-recognition is also essential so that our immune systems are appropriately defending against the right types of organisms and not attacking self, which obviously is something that breaks down in the form of autoimmune disease. So having this specificity, this non-self self-recognition is important for the proper control of our immune system and also specificity for being able to precisely recognize the pathogens that cause damage from the microbes that actually are beneficial, such as those that are in our microbiome, our commensals, those types of beneficial microbes for which we want to develop tolerance to, and not have immune responses against. So specificity, diversity are two of the traits.
And the third trait that’s actually more unique to our own immune systems is this ability to develop long-lived immunity, the ability of our immune systems to remember. We often think of memory as part of our brain and what our neurons do, but our immune system can also remember. And just instilling this long-lived immunological memory is another cardinal trait of our immune system.
So you can think about when we’re exposed to a pathogen and for the first time our bodies have two, or immune systems have two fundamental jobs that they need to do. Job number one is to fight the present infection and we need to clean up the house, we need to tame the fires, we need to eradicate that pathogen. And so fighting that present infection is obviously essential for health. Our second job though that our immune system has to do is to control the future infection. How do we protect ourselves against that same pathogen should we encounter it again? And the chances that you’ve encountered at once are very high that you’re going to encounter it again. So how do we develop this ability to protect ourselves from the present infection as well as enable our bodies to develop immunity and defenses to future infection?
Now, this has been observed in history for thousands of years. The first written observations of long-term immunity came from the Greek historian Thucydides in the early 400 BCs during the plague of Athens, where he noted that individuals who had recovered from the plague, they were able to care for the sick and they would not experience the illness again. And he noted that by saying that the same man that was never attacked twice at least fatally. So it was observed that these people could recover health, that recovered from the infection could actually not experience the same severe illness or death again. And so that was one of the first written observations of protective immunity.
But what was probably the most evident form, experimentally, was when the use of vaccination was first indoctrinated into our society. And this was the famous experiment, it was really an experiment by Edward Jenner in 1796, where he had noticed that milkmaids who developed cowpox and others had noted that they were more resistant to developing smallpox. So it was kind of observed again, that these milkmaids were immune to getting smallpox. And because he saw that the pustules of the cowpox that these milkmaids would get, the pustules looked very similar to the pustules that were observed on people who were infected with smallpox, he actually had the intuition that perhaps there was a common or similar agent that was causing these diseases because of the similarity in the manifestation of the disease and these pox blisters that would form on the skin.
And so he thought with this knowledge that perhaps that he could give somebody the cowpox virus, much to what these milkmaids were having happen just by their exposure to the cows, that if he were able to give another person cowpox that that might induce a form of immunity to the cowpox virus that would be cross-reactive, be cross-protective to the agent that caused smallpox. And this was before we understood viruses and he was able to show by immunizing then James Phipps with some of the fluid from a cowpox blister, he saw that when he did that, he put it on the skin of the little boy that a blister did form. And then he waited a couple months and did the experiment that of course cannot be done today. He then inoculated this little boy with then the scab of a blister from someone who had smallpox and tested whether or not this child got the disease, and no disease formed in this child. So this was the first evidence of vaccination, the first experimental evidence that one could use.
In this case, what was also very interesting is they use a very similar type of a virus, not the actual virus, but very similar type of virus, enables you to get cross-protective immunity to the smallpox virus. And so over the next hundreds of years then obviously trying to understand what was the cause of this immunity, what was the molecular and cellular basis of this immunity, created the field of immunology. In the late 1800s, Dr. Kitasato and Emil von Behring were some of the first to really start to identify, I guess provide evidence, that there were products in our circulation that could provide this type of immunity.
And these were experiments that they had been doing by working with diphtheria, where they would immunize with the diphtheria into animals and then they would wait, and the animals that were recovering from, were able to recover from that diphtheria infection or the toxin at that time, they could then transfer the serum from those animals into animals who had not been exposed to the diphtheria toxin. And then they were able to find that that transfer of serum that was able to provide immunity to those animals that they were then challenged with diphtheria. So there was something protective in the blood and serum of these animals that were previously exposed to the diphtheria toxin that when they were able to transfer this serum was able to protect those animals from developing disease and death. And they also did this for tetanus around the same time.
And then went through the, moving forward a few hundred years, what we were able to then discover was that the basis of this protection was the molecule which is an antibody, which is shown here on the slide, which is a beautifully shaped Y-shaped antibody that has these variable regions for detecting and binding very specifically to the parts of the pathogen that the antibodies are being formed against. And this is what forms what we refer to as the variable regions, which is where that diversity comes from. And these regions of the antibody can be different for every different type of a pathogen or a non-self protein that our immune system can recognize. This diversity is encountered because these ends of these antibodies can be different for different antibodies. And so this creates the diversity, but also the specificity, because these are able to specifically recognize these foreign antigens.
Now, these antibodies are produced by certain types of immune cells in our body, which are B cells, also called plasma cells, and these cells are essential for providing us with this humoral immunity that antibodies provide. Now, antibodies have many different ways in which they can protect, but one of the ways that is most notable is that these antibodies combined to regions of viruses such as in SARS-CoV-2, something that we’re learning a lot about today, can bind to the proteins on the outside of the virus and that these antibodies can then by binding there can inhibit that virus from binding to the cellular host proteins on the surface of our cells, such as the ACE2 protein, the receptor for SARS-CoV-2, and this can then neutralize that virus from being able to infect those cells. So these are some of the ways in which antibodies can be quite protective. And this is how passive immunity was actually used because it was able to provide the antibodies that could then coat the pathogens and prevent them from protecting.
Now, passive immunity is something that naturally occurs all the time as we breastfeed our children and the passage of antibodies from the mom to the child is something that happens all the time and is a very important process for early health in our babies and young children. So this type of passive immune therapy of serum was then widely adopted after these early discoveries, transferring both serum from people, recovered people who had been exposed to an infectious agent to people who were succumbing and having severe disease to prevent death to those infections. And also it started to be adopted with animal serum. Animals would be immunized to some of these toxins and the antibodies from these animals would then be used to treat people who were also suffering from various infections.
And so, so this form of passive immune therapy was used widely in the early 1900s. It was used for the 1918 Spanish flu, it was used for measles, it’s been used even more recently with the outbreaks of Ebola and the past SARS, and even the current SARS pandemic, some form of passive immune therapy is being used. But what’s important is to realize that this is not a vaccine, this is a treatment, because this does not provide long-lived immunity. The transfer of these antibodies that the therapy lasts only for as long as these proteins will persist in circulation of the recipient’s body. And so they usually lasts for a few weeks, but it’s not, unless you keep getting delivered, so it’s not the way in which we induce long-lived immunity.
But the reason why I wanted to bring this up was because it’s important because this is how we first started to understand what was the basis of immunity. And so passive immune therapy gave us this evidence that we do have circulating products and cells in our body that can provide immunity. And so what are those cells and how do they form? And that’s something that my lab has been interested in working on for many decades now.
You can think about the cells that give rise to this long lived immunological memory in basically two types of cells. There’s the memory B cells that we already talked about, which produce the antibodies, and the long-lived plasma cells that just, they continuously pump out antibodies once they’ve been created, because they’ve been exposed to the pathogen or to the toxin. Once they’ve been created they will continue to produce antibodies constitutively. But you also have these long-lived memory B cells that remember that pathogen that were once, that was, they were first generated against, and that they can go on to persist for long periods of time as well to remount a secondary response when it comes.
And we also have memory T cells, and these are the cell types that I work on. We have two different classes of T cells. We have CD4 helper cells, we have CD8 killer cells, and these are very important T cells to help us fight against different types of infections. CD8 T cells are very important for fighting viral infections and CD4 and CD8 combined are important for many other types of pathogens that are infected with us. But the important thing to know is that the basis of generating immunological memory, it consists of these main cell types, our memory T cells and our memory B cells, and that inducing the cells then is the ultimate goal of what a protective vaccine would do, or are using immunotherapies to modulate the functionality and the formation of these cells during an immune response.
So how do these cells form? We know how they form by studying many models of infection and also profiling now the immune responses in humans over different types of viral infections, or in vaccines, such as yellow fever vaccine and smallpox vaccine. These have been well-characterized in humans now. But the general characteristics of an immune response consists of three phases. There’s the first phase when the infection initiates and the virus, for instance, and the viral infection starts to expand, and this we refer to as the expansion phase. And while we have very few viral-specific T cells that can recognize that virus there are a small number of cells pre-existing in our body that can recognize that virus. But what these cells start to do is undergo clonal expansion and one cell will replicate to two cells, two to four, four to eight, and so on and this exponential growth of T cells will occur, and the B cells as well. I’m just focusing here on the T cells in this graph, but you’ll start to see this rapid increase in the number of cells that recognize that virus that are specific for that virus.
And this is during the acute phase of the response and of the infection. And usually for most common colds, the infection is cleared within a couple of weeks and following the resolution then of that infection with the control of the pathogen, what you see then is the second phase, which is the contraction phase. And while you generated millions and millions of these viral-specific T cells during the first phase, most of these cells are actually going to die during the resolution phase. And what you’re left with then is as you enter the third phase, which could be many weeks to many months after infection, is what we refer to as the memory phase. And this is where the formation of these long-lived memory T cells and memory B cells is occurring, is during this latter phase of the response.
So you can think of these cells that form early and develop a lot of important functions and deploy lots of weapons to eradicate the pathogen, we refer to this early phase as these effector cells, which are able to fight the present infection cause that’s their job, they’re being generated to fight the present infection. But over the course of the contraction phase, what you’re left with then is a smaller number of these cells that go on to seed the memory pool. And these memory cells then are what are used to fight the future infection. So now you can kind of see how our immune systems are able to do both job number one, to fight the present infection and job number two, to fight future infections through the course of this primary, this first exposure to the pathogen.
Now, if we look at this at a cellular level, you can see that these T-cells initially start off as what we refer to as naive, because they haven’t seen that the pathogen, that they might recognize, but upon that infection and getting activated, recognizing that pathogen, they then start to become activated, they start to proliferate and expand and, as we had talked about, developing into these effector cells, but only a very small number of these cells will survive to go on to give memory cells. And this number of five to 10% surviving has been seen reproducibly across many different types of infections. So it’s a very common attribute that you generate millions and millions of T cells during the primary infection but only a very small number of those cells go on to become your memory cells.
And that was a fascinating question. What is the reason why only a small percent of these cells are able to give rise to these long lived-memory cells? They’re endowed with this ability to provide this long-term immunity. What are the decisions and the processes that are guiding the formation of the small pool of memory cells? And many years ago, we knew the kinetics of this immune response but we didn’t know really any of the molecular pieces or parts of the pathway that were involved in making this decision of which cells were going to give rise to the memory T cells. And so many years ago we set off to try to tackle this by looking at the genes that were expressed in these long-lived memory cells versus this pool of effector cells that we knew was going to give rise to the memory cells, but most of these cells were going to die. And we were trying to ask what genes might be involved in this life or death decision that these effector cells are making to determine which of these cells were going to go on to give rise to the memory pool.
And one of the genes that we identified, and this was many years ago, but it was still a fundamental finding to the field, was a discovery that the cells, that the memory cells expressed high levels of a receptor called interleukin-7 receptor, and this was really important for the memory T cell survival. And when we started to then look more closely at these effector cells, at the expression of this IL-7 receptor, what we found was that there were indeed a subset of cells that expressed higher levels of IL-7 receptor like these more mature memory cells. And that what we found was that this was able to identify and distinguish the precursors, the progenitor cells, of this effector pool that would go on to give rise to this long-lived memory T cell population.
So during the course of this immune response, the population of effector T cells is heterogeneous, and there are some cells that are forming, but they don’t have the potential to give rise to this long-lived pool of memory cells. But there’s a small subset of cells, these memory progenitor cells, that are becoming destined and determined to give rise to this long-lived memory pool. And part of that involves the expression of IL-7 receptors.
So how do these memory progenitor cells form? If they’re important for establishing this memory pool, then how are they forming earlier in the immune response during the first few days of infection? And so by having this tool now being able to distinguish these memory progenitor cells from these other effector cells that we refer to as terminal effector cells that would die after the infection, we were able to then compare these populations and start to identify the genes that made these cells distinct from one another. And many of these genes that we found that were associated with being a memory progenitor or a terminal effector cell started to then uncover many of the pathways that were involved in the formation of these two different types of T cells that form, the memory progenitor cells and the terminal effector cells.
What this did was then to help us to elucidate the transcriptional programs that were helping to create the development of these memory progenitor cells and these terminal effector cells and these transcriptional programs ended up having opposing functions to orient these alternative fates that were being produced during this primary immune response. We also identified through the dissection of these different cell types many of the signals in the environment that are being produced during the infection that would instruct these different cells to form. And while we identified that many of the inflammatory mediators are associated with infection help to drive these terminal effector cells to form that will be very important for fighting the present infection, but again, they lose their ability to give rise to this long-lived memory pool. Many of the inflammatory mediators produced during infection will help to support these terminal effectors.
But what we also found that was very counterintuitive is that anti-inflammatory factors can actually help promote the formation of these memory progenitor cells. And so there’s a balance between inflammation and anti-inflammatory signals that help to balance this decision that creates these effector pools with these diverse fates, these different long-term fates.
And I just want to end with them thinking about how this then relates to some of the questions that we’re thinking about today, especially in light of COVID-19, which is that what are going to be the types, the right types of immunity, long-term immunity, that we need to establish with the vaccines that are going to be tested in people? And while memory T cells and memory B cells are essential for providing us with this long-term immunity, I want you to also appreciate that there’s many different types of memory T cells. And actually, what happens after our first exposure to that pathogen is that we kind of shield our body from the outside in, with lodging different memory T cells in different compartments in our body. And as you can see here, virtually every tissue in our body can harbor different types of memory T cells and some memory T cells circulate throughout our blood system, and they might go into tissues and then go back into circulation. We refer to those as circulating memory T cells. And there’s many different types of memory T cells within the circulating pool.
But there’s also a very important form of what we refer to as tissue-resident memory cells. We have some memory cells that will enter the tissue upon the first infection and they’ll remain there for very long periods of time, years, sometimes even decades after that first exposure. We see these long-lived resident memory T cells in many different tissues, largely our barriers. We see them in our lungs, we see them in our intestines, in our skin. So they can lodge themselves long-term and reside long-term in our tissues that provide barrier function, but they also are found in other internal organs, such as our brain, our kidneys, our liver. So we can see these long-lived resident memory cells in almost every tissue that’s been studied. And it’s a cooperation of these circulating memory T cells in these tissue resident memory cells that helps us again provide that shield, kind of having protection from the outside in because these memory T cells, they are our barriers, they’re there at the portal of infection. They’re right there at the frontline when that pathogen should enter and their immediate responses help to provide protection to that tissue.
So as we think about what types of memory we’re going to need for COVID-19, for protection in COVID-19, now we need to be thinking about forming the circulating memory and the humoral immunity such as what’s provided by our B cells, but also probably very important will be these long-resident memory cells, that these memory T cells that can persist in our lungs and provide protection to respiratory infections when we inhale those pathogens. And so, I think this is going to be an important aspect that we think about is what types of memory T cells are induced by COVID-19 and which types are going to be the most protective for long-term immunity to this virus?
And so with that, I just want to thank you for your time and thank my lab for all the ideas and great work that they do, and of course, funding from the NOMIS Foundation as well as the NIH, which has been essential to allow us to do this work. So thank you.