면역 체계의 이해: 선천성 및 후천성 면역

### 면역 체계의 기본 메커니즘: 세포 생물학에서 얻은 인사이트
* 🔬 제넨테크의 종양학 연구 담당 부사장인 아이라 멜먼(Ira Mellman)은 면역 체계의 세포가 면역 반응을 일으키기 위해 어떻게 함께 작용하는지 이해하는 것이 중요하다고 강조하면서 **면역 체계의 막 교통에 대한 연구**에 대해 설명합니다.
* "면역 체계의 기본 기능은 광범위한 병원균과 독소로부터 자신을 보호하고, 자기와 비자기를 구별하는 것"이며, 면역 세포가 어떻게 이러한 구별을 수행하는지 이해하는 데 수수께끼를 제공합니다.
* "면역 반응은 **공유 병원체 성분을 감지하는 선천성 면역 반응**과 **개별 병원체의 특정 항원을 인식하도록 분자적으로 만들어진 적응성 면역**이라는 두 가지 상호 연결된 팔로 구성됩니다."
* "대식세포와 식세포에 대한 메치니코프의 연구는 **세포가 병원균을 포획하고 분해하며 사이토카인을 분비**하여 더 많은 면역 세포를 모집하는 방법을 보여줌으로써 선천 면역 반응에 대한 핵심적인 통찰력을 제공했습니다."
* "톨 유사 수용체(TLR)의 발견은 세포가 어떻게 보존된 미생물 성분을 인식하고 면역 반응을 일으키는지를 보여줌으로써 **선천성 면역에 대한 이해를 혁신적으로 변화**시켰습니다."
* "항체와 적응 면역에 대한 에를리히의 연구는 면역 체계가 개별 병원체에 대한 특정 반응을 생성하는 방법을 보여주었으며, **B세포는 항원에 결합하고 제거를 위해 다른 면역 세포를 모집하는 항체**를 생산합니다."
* "B세포와 T세포의 상호작용은 적응 면역 반응에 매우 중요하며, T세포는 **MHC 분자에 제시된 항원 조각을 인식**하고 사이토카인을 분비하여 항체 생산을 강화함으로써 B세포에 도움을 제공합니다."
* 🔗 "최근에 밝혀진 세포 유형인 수지상 세포는 **선천 면역과 후천 면역 사이의 연결 고리 역할**을 하며 **항원을 포착하고 T세포를 활성화**하며 면역 반응의 두 팔을 이어주는 역할을 합니다."

제넨텍의 연구 담당 부사장인 Ira Mellman은 면역 체계의 기능과 반응을 이해하기 위해 막 트래픽을 연구합니다.

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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연구 초점: 면역 체계의 세포막 트래픽

제넨텍의 종양학 연구 부사장인 Ira Mellman은 막 교통의 근본적인 메커니즘을 연구하는 것에서 면역 체계에서의 역할에 초점을 맞추고 있습니다.

자기와 비자기를 구별하는 면역 체계의 능력은 세포 생물학적으로 해결해야 할 근본적인 과제입니다.

면역 반응은 선천성 면역과 후천성 면역이라는 서로 연결된 두 가지로 구성되며, 두 가지 모두 신체를 보호하는 데 동등하고 중요한 역할을 합니다.

메치니코프는 염증을 파괴적인 조직 발현이 아닌 보호 면역 과정으로 이해하는 데 혁명을 일으켰습니다.

그는 박테리아를 삼키는 대식세포를 관찰하여 세포 내 사멸과 세포 독성 물질의 분비에서 대식세포의 역할을 이해하게 되었습니다.

대식세포와 다른 세포에서 톨 유사 수용체의 발견은 선천성 면역 체계가 미생물을 인식하는 방법을 밝혀냈습니다.

초파리 발달과 면역에서 톨의 역할

Toll은 초기 초파리 배아에서 등쪽-배쪽 극성 축을 형성하는 데 중요하며, 이것이 없으면 배아 발생에 치명적인 결함이 발생합니다.

성체 초파리에서 톨은 IL-1 수용체와 유사하며 염증 반응을 유발하는 수용체를 통해 병원체로부터 보호하는 데 필수적입니다.

척추동물의 톨 유사 수용체는 초파리 톨과 유사한 구조를 가지고 있으며 보존된 미생물 패턴을 인식하여 선천성 면역 체계에서 중요한 역할을 합니다.

선천성 면역 반응에서 대식세포의 역할

대식세포는 다양한 병원균을 감지하고 포획하여 선천성 면역 반응에서 중요한 역할을 합니다.

식균 작용으로 알려진 이 과정은 톨 유사 수용체를 통해 침입한 미생물의 공통 성분을 인식하는 대식세포의 능력에 의해 이루어집니다.

메치니코프의 연구는 면역 체계의 선천적인 부분을 정의하는 개념적 이해와 실험적 세부 사항을 제공하여 식세포가 병원균에 대한 보호에 어떻게 기여하는지를 보여주었습니다.

적응 면역의 이해에 대한 에를리히의 기여

에를리히는 미생물 면역에 대한 반응으로 항체가 생성되는 것을 확인하여 이러한 보호 반응을 설명하기 위해 '항체'라는 용어를 만들었습니다.

적응 면역 체계는 감염된 세포를 인식하고 죽이는 항체를 생성하는 항원 특이 림프구를 통해 작동합니다.

항체는 항원에 결합하여 기능하며 보체 단백질을 모집하여 박테리아를 파괴하고 대식세포와 협력하여 미생물을 포식하고 죽일 수 있습니다.

항원에 의한 B세포 활성화 과정

림프절에서 항원과 B 세포 간의 상호 작용은 항체 분자의 발달과 생성을 자극합니다.

이 과정은 B 세포의 증폭과 항체 방출로 이어져 박테리아를 코팅하고 보체를 모집하며 식균 작용을 위해 대식세포를 끌어들입니다.

B 림프구는 면역 반응에서 중요한 역할을 하는 T 림프구의 도움을 받아 고품질 항체를 생산합니다.

T세포는 MHC 클래스 II 분자가 제시하는 항원을 인식하고 결합하여 면역 반응에서 중요한 역할을 하며, 그 후 사이토카인 생성을 자극하여 B세포 발달을 돕습니다.

T세포 수용체의 다양성은 유전자 재배열을 통해 이루어지며, 이를 통해 광범위한 펩타이드 MHC 복합체를 인식할 수 있습니다.

CD4 T세포는 MHC 클래스 II 분자를 인식하는 데 특화되어 있으며, CD8 T세포는 MHC 클래스 I 분자를 표적으로 하여 세포 내 병원균에 특이적으로 반응합니다.

바이러스에 감염된 세포를 죽이는 세포 독성 T 세포의 역할

세포독성 T세포는 감염된 표적을 향해 리소좀을 편광시켜 세포독성 화합물을 방출하여 세포를 죽입니다.

이 과정은 T세포와 표적 사이의 경계면으로 과립이 물리적으로 이동하는 것을 포함하며, 특정 유전자와 단백질에 따라 달라집니다.

T세포의 활성화에는 T세포 수용체, 공동 자극 수용체, 항원 제시 세포와의 상호 작용이 관여하며, 이 모든 것이 함께 작용하여 T세포 반응을 강화하고 면역 체계를 증폭시킵니다.

공유된 미생물 패턴에 의해 주도되는 선천성 면역 반응은 항원에 의해 자극을 받아 특정 T세포 및 B세포 반응을 생성하는 후천성 면역 반응과 함께 작용합니다.