Understanding Immune System: Innate and Adaptive Immunity

Ira Mellman, Vice President of Research at Genentech, studies membrane traffic to understand immune system functions and responses.

### The Fundamental Mechanisms of the Immune System: Insights from Cell Biology
* 🔬 "Ira Mellman, Vice President of Research on Oncology at Genentech, discusses his research on membrane traffic in the immune system, highlighting the **importance of understanding how cells of the immune system work together to generate an immune response**."
* "The immune system's basic function is to **protect against a wide range of pathogens and toxins**, distinguishing self from non-self, and providing a conundrum for **understanding how immune cells achieve this discrimination**."
* "The immune response consists of two interconnected arms: the **innate immune response**, which detects shared pathogen components, and **adaptive immunity**, which is molecularly crafted to recognize **specific antigens of individual pathogens**."
* "Metchnikoff's work on macrophages and phagocytosis provided key insights into the innate immune response, showing how cells **engulf and degrade pathogens**, as well as **secrete cytokines to recruit more immune cells**."
* "The discovery of Toll-like receptors (TLRs) revolutionized our understanding of innate immunity, showing how cells recognize **conserved microbial components** and initiate **immune responses**."
* "Ehrlich's work on antibodies and adaptive immunity demonstrated how the immune system produces **specific responses to individual pathogens**, with B cells producing antibodies that **bind to antigens** and **recruit other immune cells for clearance**."
* "The interaction between B cells and T cells is crucial for the adaptive immune response, with T cells providing help to B cells by **recognizing antigen fragments presented on MHC molecules** and **secreting cytokines to enhance antibody production**."
* 🔗 "Dendritic cells, a recently identified cell type, serve as the **missing link between innate and adaptive immunity**, capturing antigens, activating T cells, and **bridging the two arms of the immune response**."

Hi, my name is Ira Mellman. I'm Vice President of Research on Oncology at Genentech, a large biotechnology company here in San Francisco. Prior to that, though, in fact up to 2007, I was a professor at the Yale University School of Medicine, chairman of the Department of Cell Biology, and a member of the Ludwig Institute for Cancer Research. During that time and in fact up until today, my laboratory has been very interested in understanding the fundamental mechanisms of membrane traffic. In other words, understanding the movement of cells and membranes and the proteins and lipids that go to comprise those membranes, allowing them to work together to make cell shapes and cell functions of various sorts. The last, more recent period of time, though, we've become increasingly interested in trying to understand how membrane traffic acts in highly specialized cells to allow them to carry out the variety of important and specialized functions that are associated with specific and more complex systems. The system that we have chosen to work with

over the last several years is the immune system. Trying to understand how membrane traffic conspires to get cells of the immune system to work and work together to generate an immune response. It's a terrific problem of cell biology, which almost inexplicably to me, at least, has been relatively inaccessible to most cell biologists. Almost as inaccessible as cell biology has been to immunologists. But nevertheless, there is an enormous amount of very important cell biology to be learned by looking at cells of the immune system, but it also provides a lot more. It provides you with the opportunity to actually understand how events that occur at the molecular level and at the cellular level can integrate with each other at the systems level to understand a very complex and important phenomenon, which has a great great deal of relevance with respect to understanding important and very devastating human diseases. Now, in order to introduce you to the topic and let you know what it is you can indeed find out, I have to first review with you some of the basic features of what the immune response is.

and how it's organized in its cellular level of organization. So, what is the basic function of the immune system? It seems to be to be able to provide us with protection against a limitless number of pathogens and toxins that one finds in the environment. It's basically conserved in it's most elemental forms across evolution. Invertebrates have a type of immune system and certainly we vertebrates have a type of immune system, which provides us with a terrific amount of protection under normal circumstances to viruses, bacteria, protozoa, and other environmental poisons and allergens. Now, the immune system is extremely good at this, and it's also extremely clever. It can kill incoming viruses or incoming bacteria, but it does so in a fashion which avoids the injury to the host, in other words, us, which provides a really important conundrum in understanding how the immune system works. How is it that cells in the immune system can distinguish self from non-self? How can they distinguish

the normal cells and tissues of our bodies from the proteins and components that are associated with the protozoa and bacteria, and other microbial invaders that are coming in from the outside. This is probably the major fundamental and conceptual problem in understanding the immune system, and it's one that undoubtedly will have the cell biological solution associated with it. Now, is this complicated? It's absolutely very complicated, but in my view, it's not really any more complicated than anything else, and if you try and understand how the immune system works in cellular terms, through the eyes of the cell biologists, in fact, I believe it does become quite accessible. Now, it's worth the effort, as I've said already, because it's not only interesting, but it's of profound importance to understanding and controlling a wealth of important human disorders. Infectious disease is obvious, arthritis, Crohn's disease, asthma, autoimmunity, and quite possibly even cancer. Now the immune system, or immune response rather, consists of two interconnected

arms, the innate immune response, or innate immunity, and adaptive immunity. Well, innate immunity refers to that portion of the immune response, which is responsible for detecting components shared by all pathogens that we have to deal with as invaders. An interesting concept, in terms of how this might work, and not immediately obvious how it works, but indeed it turns out to be the case. Adaptive immunity is something different. Adaptive immunity refers to the type of immune response that is molecularly crafted to mold and detect individual antigens that are specific to individual pathogens and individual types of pathogens. These two work together in some rather interesting and mysterious ways that we'll go into later, but nevertheless it is important to keep it in mind that there are these two equal and equally important aspects of the immune response: innate and adaptive immunity. Innate immunity was really first discovered by this great scientist of the past, Elle Metchnikoff, shown here working in his laboratory about 100 years ago at the Institut Pasteur in Paris.

Metchnikoff's great conceptual advance was the understanding that inflammation, which is what happens after you become infected by the introduction of a bacterium or a virus. This is why your cuts become red and inflamed and hot and painful if they go untreated. This process of inflammation is a protective process of immunity and not a manifestation of the tissue's destruction. In other words, as bad as it looks, this is actually a representation of how the body is responding to invading microorganisms to rid the body of those microorganisms, rather than a reflection of the microorganism's capacity to mete out damage on the host's tissue. Prior to this point, this idea was completely foreign to scientists. Now the story goes that one of the most important observations that Metchnikoff made was actually made while on vacation on the beach with his family. And like many modern-day scientists who bring their computers with them on vacation, Metchnikoff in the age before computers brought his microscope and studied the reaction of starfish larvae to the introduction of foreign materials.

such as bacteria introduced experimentally into the larvae. What Metchnikoff found was that a series of cells would come in and surround the bacterium, and in fact, quite visibly, engulf these microorganisms shown here as these red oblong creatures, contained within this cell. He named these cells macrophages, because they were large cells that ate bacteria. Macrophage: large eater. The bacteria were taken into the interior of the cell, and Metchnikoff further found that if he stained these cells with a dye that partitioned into acidic elements within cells and other things, the bacteria stained red, further indicating to him, and in fact correctly to us, that the bacteria after they entered into the cell would be delivered to an acidic intracellular compartment, which we now understand and know as lysosomes. Now bear in mind, this was well over 100 years ago, and long before even membranes were truly discovered. Now these bacteria eventually stopped growing, they died after being taken up by the cells, and eventually disappeared.

and Metchnikoff further understood that as a process of degradation. So, what actually happens when a macrophage eats a bacteria or encounters a bacteria is shown here. The response is not only limited to the uptake and intracellular killing of the bacteria, but also these cells secrete a variety of important cytotoxic agents, degradative enzymes, as well as protein hormones referred to as cytokines. Cytotoxic agents include important mediators, such as hydrogen peroxide, which is a common disinfectant that is used, but macrophages do this on their own, as well as other types of active forms of oxygen. They secrete an enzyme called lysozyme, which is quite adept at degrading the cell walls of incoming bacteria, and a series of lysosomal enzymes contained within the lysosomal structures of these cells that basically degrade all sorts of other things. As I mentioned, the cytokines that are released by cells, by macrophages after encountering bacteria, some of which you may already know, such as the molecule interferon.

macrophages are a prime source of interferon. They have the effect of recruiting more macrophages and other cells of the immune system to the site of bacterial invasion, increasing the overall level of inflammation, but again, not for the purpose of tissue destruction, but rather to recruit more and more cells of greater complexity and of increased levels of sophistication that help deal with the infection and hopefully eradicate it before it gets out of hand. Now why is it that macrophages and other cells of the innate immune system, such as neutrophils, know to respond to microorganisms? What is it that they are recognizing? So here the story turns to a relatively recent observation having to do with a class of membrane protein receptors found on macrophages as well as other cells, called Toll-like receptors. What are these? The story actually starts a little bit earlier than that, in the work of Catherine Anderson and Carl Hashimoto, who identified the activities associated with a well-known gene in Drosophila called Toll. Now Toll was originally identified

as acting in early embryonic development in Drosophila, specifying the dorsal from the ventral pole of the early Drosophila embryo. Toll was known to bind to a ligand, called Spaetzle, which activated the Toll-receptor, sending a signal to the embryo allowing this dorsal ventral polarity axis to be established. Here you can see some embryos that either do or do not express wild-type Toll, or members of the pathway. In panel A, all the way on your right, you can see what the normal embryo looks like, and in the absence of functional Toll-receptor or an active Toll-like pathway, you can see that these embryos completely disorganized, and they don't develop, and it is known as a lethal defect early in embryogenesis. Now Toll, it turns out, also has a role in the adult fly, a quite different role, but one that is no less important insofar as the fly is concerned. Here a different group of investigators, led by Bruno Lemaitre and Jules A. Hoffmann, found that Toll was absolutely

required in order to protect adult Drosophila from their pathogens. In this case, what you are looking at is a poor dead fly that was unable to combat the fungal infection that you can see here, growing almost as a beard or a beard of death around this fly's torso because of the absence of a functional Toll receptor in the fly as the adult. This is really one of the very, very first indications that Toll has a role outside of early morphogenesis and also plays an important role in host defense. Now how does it do this? Here is a diagram of what the Toll receptor looks like in flies. It has a nice extracellular domain with some repeats. It has an intracellular domain that one can presume has signaling molecules or signaling features associated with it, but one of the most interesting features that fell out of the analysis of what this receptor looked like was that it was very, very similar to a receptor for cytokine called IL-1. Again, another product of the macrophage. And specifically where it was similar

was in the cytoplasmic domain, here in the case of Toll, and here in the case of IL-1 receptor. Since it was known that stimulation of IL-1 receptor turned on an inflammatory response from other sorts of studies, it was surmised that indeed the Toll-receptor did much the same thing. So in subsequent years, when Charlie Janeway and his colleagues started looking for the expression of these receptors in vertebrates, they found indeed that there is a whole family of Toll-receptors, and indeed well over a dozen of them are now known that have the same basic organization as Toll does in Drosophila, with an extracellular domain that is similar in many ways, but most importantly the cytoplasmic domains that have a large degree of homology to the Toll-receptor in Drosophila, as well as to the IL-1 receptor. Now what these receptors do, and the reason they are so many of them, is that each one has a specificity for a different microbial component.

In each case, the microbe itself needs those components to survive. So here, Toll-like receptors are expressed on the plasma membrane, such as Toll-receptor four, or TLR-4, and TLR-5. See various important components associated with bacteria. So, TLR-4 sees components associated with the peptidoglycan, a lipopolysaccharide component of bacterial coats. TLR-5 sees a major protein associated with bacterial flagella, both of which are components that are absolutely needed by these bugs in order to survive. They are shared by great many types of bacteria, hence these Toll-receptors recognize these conserved molecular patterns and act as the innate immune system sensor. Another set of Toll-receptors are actually found in intracellular vesicles, endosomes, and lysosomes found within macrophages and other cells, examples here are TLR-7, TLR-8, and TLR-9. And they have a tendency to recognize nucleic acid components such as double-stranded RNA, DNA, and single-stranded RNA.

which are associated with other types of incoming pathogens, such as both enveloped and non-enveloped viruses. So here you have a complete pattern of conserved receptors that have this remarkable capacity to be able to detect, again, the shared components that can be found with a wide variety of different types of incoming and invading microbes, turning on the macrophages, and in fact, any other cell that happens to be expressing them. Now the way that this turn-on takes place, or the way that this signaling occurs, perhaps not surprisingly, is similar to the way that stimulation of IL-1 receptor, the cytokine receptor, does it, turning on a series of signaling intermediates leading into the nucleus, activating I think the most important and simplest element, the so-called Nf-kappa-B pathway, which leads to in turn a great number of events that prime almost everything important that happens in the context of an innate immune response. So intracellular signaling pathways are all activated by TLR receptors. The pathways themselves can be different from TLR to TLR, as they can from cytokine to cytokine.

but this really summarizes the basic feature of how the system works. Now, the consequences of it are shown here. Here, what you are looking at is a video of macrophages that have been given yeast to play with, and what you can see is that the macrophages move towards the yeast and then engulf them. So here is one that is moving directly towards it and engulfs it. Here is another yeast that is here, which will eventually be attacked and eaten by another macrophage, shown right there. So, in much the same way that Metchnikoff found these invading microorganisms activated the macrophage, turned it on, increased its capacity for migration, its capacity for cytotoxic killing, and as shown here, its capacity for actually killing and eating the invading microorganisms. This is another movie showing that the process of phagocytosis of these yeast, or in fact any other large particle that a macrophage encounters, is intimately associated with the ability of the macrophage to polymerize actin.

as a motile cytoskeletal component directly underneath where the particle binds and turns on itself, growing out long pseudopods that engulf the particle, capturing it and bringing it inside the cell, and eventually getting it to fuse with lysosomes, again shown here. So what you are looking at in this particular video is a particle that is entering a macrophage, whose surface is stained green, and shortly after internalization, this green membrane turns red as a consequence of fusing with these red endocytic vesicles that are found inside the macrophage. Again, showing that very high tech components, which Metchnikoff knew over 100 years ago, which is that macrophages can detect, can bind, internalize, and deliver to lysosomes for purposes of degradation those incoming bacteria and other sorts of pathogens that are found in the outside world against which we need protection. So to summarize then, Metchnikoff really has to be credited with providing us a great deal of not only conceptual understanding, but in many ways even

experimental detail that has defined for us the innate arm of the immune system. The system that recognizes shared pathogen-derived components that are recognized by Toll-like receptors, as well as a variety of related receptors that we won't have a chance to talk about. And it is powered to a very large extent by cells, which are referred to collectively as phagocytes, and these include the macrophage, which are the large cells that Metchnikoff first identified, as well as neutrophils, or granulocytes, polymorphonucleocytes, which are actually smaller than macrophages, and indeed Metchnikoff had seen these too, he referred to them as microphages. These mediated protection by activating cytotoxic mechanisms, and as you have seen, quite graphically, by actually physically eating, clearing, and degrading extracellular bacteria and other types of microorganisms. Now, almost at exactly the same time that Metchnikoff was working, elsewhere in Europe, another terrific scientist, Paul Ehrlich, was also hard at work.

and you can tell from this image that Ehrlich was a terrific and great scientist because he has one of the hallmarks of great scientists, which is an incredibly messy office. So here he is sitting, reviewing some notes, and what Ehrlich's contribution was, was to show for us how the other main arm of the immune system was organized and what it did. This is called adaptive immunity. What Ehrlich identified was that individuals, whether it be the humans, it be the animals, that are immunized with various types of microorganisms or bacterial derived toxins, make a response in the blood that is inherently protective, and in fact Ehrlich coined the term antibodies to describe this response, which has the ability, obviously, of protecting us against whatever it is that had entered into our systems or into our bloodstreams. Antibodies see individual antigens that are specific to individual pathogens types, so if you immunize with one type of bacteria,

you will not necessarily make antibodies that will recognize and protect a second individual against another type of bacteria. So, in this way, the system is fundamentally different from the innate immune system. It's crafted in a molecular fashion to the molecular entity that happens to be coming in. The way the cellular mechanism, whereby the adaptive immune system works, is using not so much macrophages, as we know now, but rather making use of antigen-specific lymphocytes that indeed make these antibodies that recognize and kill the infected target cells either separately from, or as you will see in a minute, in conjunction with the macrophages. This is what an antibody molecule looks like in crystal structure. It consists of two major parts: a Fab fragment and a Fc fragment, both of which are linked together. The molecular weight is about 150,000 Daltons and consists of four chains: two light chains, shown in red, and two heavy chains shown in yellow and in blue. The antigens themselves actually bind to the so-called Fab regions of antibody.

molecules demonstrated in this diagram out near the tips. So here you find a great deal of sequence variation that allows the antibody to form complementary structures allowing it to interact quite specifically with whatever antigen comes into an organism against which an antibody can be made. Now how antibodies work. After recognizing their antigen, they are made, and as shown here they'll bind to the antigen. In this particular example, that antigen is present on the surface of the bacterium, and one of the simplest ways in which the antibody can work to kill the bacterium is to recruit another set of proteins that are found in our plasma, called complement, which actually is a number of proteins, not just one. Complement is recruited by antibodies, inserted into the bacterial membrane, causing the bacterium to lyse. Now in addition, these antibodies will work together with an element of the innate immune system, macrophages in particular, but also neutrophils. Macrophages are probably more important since macrophages actually have receptors for the Fc domains of these antibodies.

which have some of the same effects that Toll receptors do. In other words, binding of antibody-coated microorganisms to macrophages will trigger the release of the same types of cytotoxic compounds that we've already discussed, and also trigger the ability of the macrophage to mediate phagocytosis and intracellular killing and destruction of these antibody-associated or antibody-coated microorganisms. So here you have this nice example of the innate system working together with the adaptive immune system. Now, antibodies are not made by macrophages, although that was an idea that was originally thought of by Metchnikoff and by Ehrlich, who, by the way, shared the Nobel Prize for their discoveries back in 1908, 100 years ago this year. Antibodies instead are made by lymphocytes, a particular class of lymphocytes, as many of you know, I'm sure, called B lymphocytes. B lymphocytes exist in great number found throughout a variety of lymphoid tissues in the body and have a repertoire

of potential interactions. In other words, due to inherent and preexisting variability in that small Fab region, or complementarity determining region found in the Fab region of antibody molecules, incoming antigens can find or B cells rather with the right specificity can find and actually bind to antigens associated with bacteria, or antigens that are simply with soluble proteins. And the simple act of binding of the antigen to the antibody, which at this point in a B-cell's development is actually a membrane protein receptor on the B-cell, is sufficient to simulate development of the B-cell and finally the production of an amplification of more and more of these antibody molecules. Now this is a video that shows you how the system works when you get a sore throat, which is indicated here in red. What that's again a manifestation of, as Metchnikoff told us, a protective response, not a destructive response. So here you see bacteria lining the surface of your throat following an infection and these bacteria are putting off a variety of protein antigens that are associated with these bacteria.

so not only have you generated an innate immune response, but now these bacterial-specific antigens are being released. And what happens to them is that they begin to drain into the intercellular spaces that one finds in all of your tissues, referred to as the lymph. The lymph drains into the lymphatics, which then comes into these nodes, or specifically lymph nodes, that monitor every 24 hours a day what proteins, what antigens, what bacteria have entered into the lymph. So here you see our bacterial protein entering into the lymph node, and what they encounter here are the wide array of lymphocytes and other cells. And here you can see them in a higher magnification, and as our bacterial-derived proteins come in, they filter through these millions or billions of cells, as you can imagine, and cells that are B-cells that may detect a component of that antigen will bind to it based on these antibody molecules or via these antibody molecules that are intercalated as membrane proteins on the surface of these early B-cells shown here.

clicking on, and this will then hit onto another B-cell receptor, and a third, and a fourth, until enough of them come together to actually generate a signal to the B-cell, which says that I have now detected the antigen I was born to detect and as a result, it is now time to start making more of myself. So these B-cells become very active and begin to develop and divide. The affinity that they have for the individual antigens, in essence, increases as B-cells with increasingly large affinities, increasingly great affinities for antigens, compete with each other to bind more and more. So here you see a clone of B-cells that gives rise to a larger number of itself, and then as you can see here, in this representation, antibody molecules begin to be released into the extracellular space, and here is just an indication of the secretory event that takes place, very similar to that which is described in another of the iBioseminar science series given by Randy Schekman.

Now here, the antibody molecules at this stage in development are actually pentamers, coming back, homing to the bacteria, coating them with antibody molecules, recruiting complement, and, as shown here, also recruiting macrophages, which again, just as Metchnikoff has already shown us, will come and eat those bacteria that are coated with antibody, taking them up by phagocytosis, killing them, and degrading them. Now it turns out that things are not that simple, of course. What I've just shown you in that video isn't in every sense correct, but it turns out that B lymphocytes make the best antibodies when they are helped by another type of lymphocyte, referred to as T, or thymus-derived, lymphocytes. And the way that works is that here you can see an extracellular antigen coming, binding to the surface antibody molecule of B-cells, and then it turns out that the antigen is internalized by endocytosis into the B-cell, and a small fragment

of this antigen is cleaved off and is bound to a molecule referred to as a major histocompatibility class II molecule, or MHC class II molecule. This complex of the peptide plus the MHC class II molecule is then recognized by a preexisting T-cell, which has a different type of antigen receptor referred to as the T-cell receptor, again which has a great deal of diversity built into it as a consequence of the development of T-cells in the early development of the immune system. What the T-cell then does is to secrete, again, our friends, the cytokines. In this case, a class of cytokines which helps the B-cell develop, helps them divide even more, and helps them create antibodies with ever-increasing affinity. Now the way the T-cell system works is illustrated in a little bit more detail here. T-cells come in two general flavors, and we'll come back to this later, CD4 T-cells, as well as CD8 T-cells. We've been talking about CD4 T-cells.

which recognize bacterial or other derived peptides bound to these so-called MHC class II molecules. They do this by the virtue of having these T-cell receptors, which again have their own specificities associated with them, such that by random chance, the appropriate T-cell receptor is made for this particular complex of peptide and MHC class II. Diversity in the T-cell receptors, rather than being so much generated by mutation, which is what occurs in the antibody in the B-cell system, occurs by rearrangement of the T-cell receptor gene. Again, rearrangements that cause a greater number of potential combinatorial sequences that can recognize a wide array of these peptide MHC complexes. So that said CD4 T-cell sees MHC class II molecules to a large extent because it makes the second membrane protein called CD4, which also recognizes the MHC class II molecules, but recognizes an invariable portion of those molecules. CD8 T-cells express exactly the same type of T-cell receptors.

but they're targeted to a different type of MHC molecule. In this case, a MHC class I molecule. And the reason this particular targeting takes place is because the CD8 membrane protein found on the CD8 T-cell recognizes the class I molecule and not the class II molecule. So very complicated. And this is obviously a simplistic view of how this works. But at its most elemental form, this is how T-cells cooperate with B-cells and in fact with a variety of other cells as well. Now CD8-restricted T-cells, or those T-cells that see antigens bound to class I in general, don't see antigens that are coming in from the outside. In much the same way, or at least I should say, analogous to what happens in the case of Toll-like receptors that are expressed either on the surface of a cell or inside, the CD4/CD8 system, or class I and class II MHC systems are adapted to incoming pathogens that reveal themselves either on the outside world or on the inside world. The CD8 system and the class I system

take care of those things that are going on in the inside world. So when viruses infect our cells, those viruses almost invariably work by binding to receptors on the surface of the cell and fusing, or entering, the cell either at the level of the plasma membrane or following entry into endocytic vesicles, and then breaking out into the cytoplasm. That type of endogenous pathogen, because you can now refer to it as endogenous, because it's found inside the cell, that type of pathogen is treated by the immune system to generate peptides that are then loaded onto class I, as opposed to class II, molecules. Now the way these T-cells work, again, is somewhat analogous to what one finds in the innate immune system, except that it is all very specific and very antigen-driven. So here you are looking at a cytotoxic CD8 positive (+) T-cell. This is work of Julian Griffin at the University of Cambridge in England, and what Julian has noticed, as well as others over the years, is that these cytotoxic CD8+ T-cells, when they recognize

a virus-infected target in fact polarize all of their lysosomes, which actually now are differentiated to contain a wide variety of cytotoxic compounds, towards the infected T-cell. These granules line up at the interface, or synapse, between the T-cell and the target, and are eventually released, killing the target. This is what you are looking at here in an electron micrograph also from Julian's work. Here you can see these cytotoxic T-cell, or CD8 T-cell, or CTL granules in the region of the cytoplasm that is very very close to the infected target cell. These granules contain lysosomal enzymes, various lytic enzymes, ligands such as Fas and receptors that will induce apoptosis or cell death in the target, and also perforating molecules called perforins among others that will punch holes in the target cell. All leading to its rapid death. So in other words, the virus has infected this cell, think its safe by existing within the cell and then the cytotoxic

T-cell comes along and recognizes a peptide derived from the virus, releasing the granules at the site of the infected cell, thereby killing the cell. This is just the diagram showing how this process works. In fact, over the last several years, as a consequence of interrogating some important mutations that lead to defective CD8 T-cell responses, which Julian and others have shown, is that these granules actually have to physically polarize by moving on microtubule tracks from diverse places within the cytoplasm to this interface, this synapse, between the T-cell and its target. In the absence of genes that are required for the translocation of these granules to this point in the cell, Rab proteins, microtubule binding proteins, etc., these T-cells are incapable of docking with or incapable of fusing with the plasma membrane of the T-cell close to the target. Again, emphasizing one critical element of where membrane traffic plays a major role in allowing the immune system to conduct its job.

Now, how does this all work? We've discussed already a bit how TLRs activate cells, such as macrophages, in the innate immune system. T-cells become activated in two very important ways. The T-cell receptor itself is a signaling molecule, recruiting tyrosine kinases to its cytoplasmic domain after it recognizes its ligand, which as we've been discussing is a complex of peptides plus MHC molecules. But also, a variety of other interactions take place. So-called co-stimulatory receptors, which are other receptors that are present on the surface of T-cells, recognize a variety of other molecules that can be found on the surface of infected cells or on B-cells or on other cells of the immune system, that send further signals to the T-cell, enabling it to more effectively do its job and also amplify its own numbers in a way that is selective and antigen-driven, quite analogous to what happens in the case of B-cells. Further, selected cells in the immune system

which are referred to as antigen-presenting cells or APCs, which we'll come back to in a later lecture, are capable of secreting their own sets of cytokines, which have the effect of further accentuating and enhancing T-cell responses. So here we have two aspects, two critical aspects of the immune system. Innate immunity, which is characterized by direct cellular responses to pathogens by detecting shared microbial patterns, that is not antigen specific, working together hand in glove with Ehrlich's observation of the adaptive immune response, which generates specific antibodies to variable antigens, and occurs as a consequence of an antigen stimulation of T-cells and B-cells. These two things, as I've already intimated to you, are connected, but they're connected in even a more intimate fashion, which we'll turn to in the next lecture, provided by a recently identified cell type referred to as the dendritic cell, which really we now understand provides the long sought-after missing link between the innate and adaptive immune system.

Ira Mellman (Genentech) Part 1: Cellular Basis of the Immune Response

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Science Communication Lab

Research Focus: Membrane Traffic in the Immune System

Ira Mellman, VP of Research on Oncology at Genentech, has transitioned from studying fundamental mechanisms of membrane traffic to focusing on its role in the immune system.

The immune system's ability to distinguish self from non-self is a fundamental challenge that may have a cell biological solution.

The immune response consists of two interconnected arms: innate immunity and adaptive immunity, both of which play equal and important roles in protecting the body.

Metchnikoff's Discovery of the Immune Response

Metchnikoff revolutionized the understanding of inflammation as a protective immune process, rather than a destructive tissue manifestation.

His observation of macrophages engulfing bacteria led to the understanding of their role in intracellular killing and secretion of cytotoxic agents.

The discovery of Toll-like receptors on macrophages and other cells shed light on how the innate immune system recognizes microorganisms.

The Role of Toll in Drosophila Development and Immunity

Toll is crucial for establishing the dorsal-ventral polarity axis in early Drosophila embryos, and its absence leads to lethal defects in embryogenesis.

In adult Drosophila, Toll is essential for protecting against pathogens, with its receptor being similar to the IL-1 receptor and triggering an inflammatory response.

Toll-like receptors in vertebrates have a similar structure to Drosophila Toll and play a role in the innate immune system by recognizing conserved microbial patterns.

The Role of Macrophages in the Innate Immune Response

Macrophages play a crucial role in the innate immune response by detecting and engulfing a wide variety of pathogens.

This process, known as phagocytosis, is powered by the ability of macrophages to recognize shared components of invading microbes through Toll-like receptors.

Metchnikoff's work provided a conceptual understanding and experimental detail that defined the innate arm of the immune system, demonstrating how phagocytes contribute to the protection against pathogens.

The Contribution of Ehrlich to the Understanding of Adaptive Immunity

Ehrlich identified the production of antibodies in response to immunization with microorganisms, coining the term "antibodies" to describe this protective response.

The adaptive immune system works through antigen-specific lymphocytes that produce antibodies to recognize and kill infected cells.

Antibodies function by binding to antigens and can recruit complement proteins to destroy bacteria, as well as work with macrophages for phagocytosis and killing of microorganisms.

The Process of B-Cell Activation by Antigens

The interaction between antigens and B cells in the lymph nodes stimulates the development and production of antibody molecules.

This process leads to the amplification of B cells and the release of antibodies to coat bacteria, recruit complement, and attract macrophages for phagocytosis.

B lymphocytes produce high-quality antibodies with the help of T lymphocytes, which play a crucial role in the immune response.

The Role of T-Cells in the Immune Response

T-cells play a crucial role in the immune response by recognizing and binding to antigens presented by MHC class II molecules, which then stimulates the production of cytokines to aid B-cell development.

The diversity of T-cell receptors is achieved through gene rearrangement, allowing them to recognize a wide range of peptide MHC complexes.

CD4 T-cells are specialized in recognizing MHC class II molecules, while CD8 T-cells target MHC class I molecules, specifically responding to pathogens within the cells.

The Role of Cytotoxic T-Cells in Killing Virus-Infected Cells

Cytotoxic T-cells polarize their lysosomes towards the infected target, releasing cytotoxic compounds to kill the cell.

The process involves the physical movement of granules to the interface between the T-cell and its target, and is dependent on specific genes and proteins.

The activation of T-cells involves the T-cell receptor, co-stimulatory receptors, and interactions with antigen-presenting cells, all working together to enhance T-cell responses and amplify the immune system.

The innate immune response, driven by shared microbial patterns, works alongside the adaptive immune response, which is stimulated by antigens to generate specific T-cell and B-cell responses.