Session 1: Introduction: Which Cells Are the Players?

Transcript of Part 2: The Immune System

00:00:06.19	Hi, my name is Ira Mellman. I'm a scientist at Genentech,
00:00:10.02	which is a biotechnology company here in San Francisco.
00:00:12.24	I study cancer, but I also study the immune system, so I'm happy to be here today
00:00:17.00	to tell you something about the immune system, what it is, and how it works.
00:00:20.11	It is really not as complicated as a lot of us fear.
00:00:23.16	Now, what is the function of the immune system?
00:00:26.05	Now, it turns out that in our daily lives we are surrounded by a wide variety of pathogens.
00:00:32.00	Bacteria, viruses, other little organisms that cause an almost limitless number of infections in us,
00:00:38.26	in humans, and we need to be protected against these environmental pathogens,
00:00:42.16	and toxins that they make, on an almost continuous basis. Every time we breath, we take in bacteria or viruses,
00:00:49.15	every time we drink or eat something,
00:00:51.29	also, we have the potential of taking in viruses and bacteria
00:00:56.01	and obviously we don't get infected and sick as a consequence of just daily life on a routine basis.
00:01:01.11	And the reason that happens is because we have immune systems to protect us
00:01:04.22	against all of these pathogens and toxins.
00:01:07.27	Now, the immune system has to work in a very special way though.
00:01:10.24	Although it's very powerful at being able to rid us of all sorts of noxious organisms,
00:01:15.16	it has to be able to understand who is foreign, in other words, who are the pathogens
00:01:20.13	that are trying to infect us, and distinguish those pathogens from our own cells.
00:01:24.15	So, all of this has to occur, without avoiding injury to the host, which is us.
00:01:29.04	To do that, what the immune system has to do, and this is the complicated part,
00:01:34.13	is to distinguish self from non-self, in other words, distinguish the invaders from that which it is trying to protect,
00:01:42.15	which, again, is us, so this is a very, very important feature of the immune system,
00:01:47.01	and means that it's actually really highly specialized, and in many ways, really smart
00:01:51.24	to be able to tell the differences, and I'll touch on some of the ways in which the immune system does this.
00:01:56.28	Now, it turns out that all multicellular organisms have immune systems,
00:02:00.16	whether they are animals, humans, fish, insects or plants.
00:02:05.16	The degree of complexity of the immune system, as you go through different types of organisms
00:02:10.29	that you find on earth, is entirely different, where, you know, humans and dogs and cats
00:02:17.07	have much more complicated ways protecting themselves than do plants and insects,
00:02:23.00	but nevertheless, the same basic principle is conserved throughout evolution,
00:02:27.12	and in fact, you can find even the most primitive types of immune responses, and immune systems,
00:02:32.19	that one can see in even organisms as simple as insects,
00:02:37.04	and also playing a very, very important role in protecting us against the very same pathogens that insects have to be protected against.
00:02:43.19	Now, as I said, immune response is complicated,
00:02:47.18	yep, that's true, but it's really not that much more complicated than anything else in biology
00:02:51.25	and if you break it down in terms of the cells that are involved, that actually make it work,
00:02:57.13	it's a lot easier to understand.
00:02:59.18	Now, it is important to understand, not only because, as I already told you,
00:03:04.02	on a day-to-day basis we have to protect ourselves against invading pathogens,
00:03:07.15	but also, many, many important diseases, such as infectious disease, as we've already been discussing,
00:03:13.07	or AIDS, or asthma or lupus, autoimmune disorders, or even cancer, and various allergies,
00:03:19.10	are caused by breakdowns, or at least are aided by breakdowns of the immune system
00:03:24.17	and as a result, in order to really understand the basis for these diseases
00:03:29.29	and understand their biology, we have to know something about how the immune system works.
00:03:34.22	So, what is the immune system anyway?
00:03:38.04	It's very, very simple, in very, very simple terms, it's a system of specialized cell types
00:03:43.16	that are mostly derived from the bone marrow. I'm sure all of you know what the bone marrow is,
00:03:47.21	especially in long bones, such as shown here,
00:03:49.26	you find a factory of cells that produce many, many types of cells that are found throughout the body.
00:03:57.11	These are called, in the first instance, the most popular and populous of them are called lymphocytes,
00:04:02.22	which come in two basic flavors, T cells and B cells.
00:04:06.20	There are also cells known as macrophages, and dendritic cells and monocytes
00:04:11.06	and K cells, granulocytes, each one of them has a very, very specific function
00:04:15.22	in helping us to protect ourselves against invading pathogens.
00:04:19.22	All of these cells together are called the immune system
00:04:24.00	and they're found all over the place.
00:04:26.10	So, they may form themselves in the bone marrow, but they then span out through the blood
00:04:31.15	and into virtually every tissue that we find in the body.
00:04:34.24	Here, what you're looking at is a picture of skin, which has one type of immune cell in it, called a dendritic cell,
00:04:41.18	which basically sits in the skin waiting for invading pathogens to come,
00:04:45.14	for example, after you cut your finger or something like that,
00:04:49.12	a bacteria will enter into the cut and that bacteria will be detected and recognized by the dendritic cells.
00:04:55.21	The dendritic cells, as I'll show you in a minute, will leave the skin
00:04:59.05	and then migrate elsewhere, through a system of little tubes and vessels, totally separate from your blood vessels,
00:05:06.09	but basically doing the same sort of thing.
00:05:08.14	And this is called the lymphatic system, or lymphatic vessels.
00:05:12.20	These are small tubes, as I said, that are found literally everywhere,
00:05:18.15	lymphoid cells enter into the lymphatics, and start migrating.
00:05:24.08	Where do they go? They migrate and then congregate in a series of small lymphoid organs,
00:05:30.07	well, some of them are not so small, like the spleen, which is found in your abdomen,
00:05:33.19	but the small ones, and in fact probably the most important ones,
00:05:37.11	are called lymph nodes. Now, lymph nodes are little aggregates, and I'll show you this in a minute,
00:05:42.11	of cells of the immune system that have very, very special functions
00:05:47.00	and very, very important activities to perform, but you can find them on yourself, throughout your body,
00:05:52.23	on your arms, legs, chest, everywhere else, but probably most typically,
00:05:57.25	if you just feel on your neck, particularly after you have any type of an infection,
00:06:02.29	such as a sore throat, you can find these little bumps that are there.
00:06:06.26	And I'm sure you probably, many of you know that these are lymph nodes,
00:06:10.11	but this is basically what they do, they're just not there sitting there, they're actually all connected together
00:06:15.13	in a very complex system that is again totally parallel to what's going on in the blood.
00:06:20.12	So, they really exist only to transport cells of the immune system from your peripheral tissues,
00:06:28.14	from your fingers, back to the lymph nodes where they can find other types of immune cells.
00:06:35.12	Now, this is a blow-up of what actually happens in a lymph node.
00:06:40.29	Precisely what happens here at the moment is not really important,
00:06:43.20	but I want you to look at is the fact that you see a great and high concentration
00:06:49.01	of all different types of cells of the immune system, particularly lymphocytes and dendritic cells,
00:06:54.01	that all are talking to each other and basically what they do
00:06:57.16	is they are communicating and trading information on what they encountered in the tissues:
00:07:04.07	what types of pathogens were there and decide among themselves essentially what to do about them.
00:07:10.22	So, these are centralized processing centers in which information about invading pathogens
00:07:18.05	is communicated to different cells that have different functions than actually mounting a protective response
00:07:24.28	against a particular pathogen type.
00:07:27.18	Now, the immune system system consists of two interconnected arms
00:07:31.22	that we call the innate immune system and the adaptive immune system.
00:07:36.01	Innate immunity is the most evolutionarily ancient and is found in insects,
00:07:42.27	in fact, it was first found in insects,
00:07:45.07	and is responsible for detecting components that are shared by virtually all pathogens.
00:07:51.06	So, although there are many, many different types of bacteria,
00:07:53.25	they do have a lot of very fundamental things in common,
00:07:56.24	and the innate immune system evolved to be able to recognize those things that are fundamentally the same
00:08:01.15	from one bacteria to another or from one virus to another or one protozoan parasite to another.
00:08:08.25	Regardless of what their species actually is.
00:08:12.13	The adaptive immune system, though, recognizes those things that are really very specific
00:08:17.08	and very special to an individual pathogen and requires a greatly more amplified
00:08:23.26	and complex series of events to take place at the cellular level in order to allow that type of specificity to take place.
00:08:31.08	These two systems work very, very closely with each other, hand in glove,
00:08:36.04	and how they connect one to the next has only recently been worked out
00:08:40.27	and it turns out to reveal yet another fundamental part of the immune system
00:08:45.12	which is the missing link between the adaptive and the innate immune responses
00:08:49.24	and we'll get to that just in a minute.
00:08:51.02	But just to give you a hint, that's what dendritic cells do.
00:08:55.07	Now, our understanding of how the immune system works really dates back into the 19th century,
00:09:02.16	really to the work of two scientists, the first of whom is shown here, this is Ellie Metchnikoff,
00:09:08.22	who really made a very, very important conceptual understanding,
00:09:12.11	which is that when you see an infection, particularly infection that would occur in the skin,
00:09:17.14	the swelling and the redness and the heat and the pain, and all of this stuff that occurs,
00:09:22.25	that we know is characteristic of infections, is not really an indication of tissue being destroyed,
00:09:29.05	but actually is an indication of the immune system, particularly the innate immune system,
00:09:34.08	trying to do its job, and trying to kill of the invading bacteria.
00:09:38.00	One of the cells, and perhaps the most important one, that Metchnikoff found is the cell called a macrophage
00:09:44.04	and this is one of his original drawings showing what a macrophage looks like.
00:09:48.02	You can see a cell with these long tentacles hanging off the ends of it,
00:09:53.03	plus a lot of structures inside the cell, some of which are colored red,
00:09:57.19	which are actually the intracellular destructive bodies
00:10:00.14	that are to a very large extent responsible for killing and then destroying invading bacteria.
00:10:07.19	And all of this Metchnikoff found out just with very, very crude microscopes
00:10:11.04	and very, very simple techniques, in fact, probably a lot simpler than what's available now
00:10:19.02	in even junior high schools and high schools everywhere,
00:10:22.23	he was still able to work this out.
00:10:24.20	As I said, microorganisms such as bacteria are recognized by macrophages
00:10:29.28	and they are killed, they are taken up, they're ingested by macrophages
00:10:33.14	and this process all enhances the protective immune aspect of what macrophages do
00:10:41.20	and starts the process of inflammation,
00:10:44.15	and inflammation is really the process whereby one cell, after detecting a pathogen,
00:10:49.23	signals to its neighbors that there's something going on, and as a consequence, more cells come in to help out.
00:10:56.25	Part of the reason that inflammation takes place
00:11:00.16	is because the act of killing bacteria involves a lot of agents that really serve as signals
00:11:07.10	that attract other cells of the immune system.
00:11:09.28	So, I've listed some of the more important ones here,
00:11:12.02	cytotoxic agents occur, so that macrophages can make large amounts of hydrogen peroxide
00:11:17.18	which actually is quite effective at killing most bacteria.
00:11:20.23	They secrete enzymes or expose the bacteria to enzymes that will degrade the bacteria themselves,
00:11:29.05	and then also, finally, they will release these inflammatory components,
00:11:33.19	which in the business we call cytokines, that are small proteins or hormones
00:11:39.06	that are released by the macrophage, rather, that attract other immune cells to the site.
00:11:44.29	Now, why is it that macrophages and in fact other similar immune cells are able to do all of this?
00:11:51.23	How can they even know when a bacterium is present,
00:11:54.28	so as not to turn on all of this inflammatory activity when only normal host cells are around?
00:12:01.29	Well, that's because they have a series of receptors
00:12:05.02	on the surface that are really very specialized for being able to understand when bacteria are present.
00:12:12.13	These are called Toll-like receptors which, rather interestingly,
00:12:17.10	were first discovered not because they had anything to do with bacteria,
00:12:20.18	but because they had something very important to do with the earliest stages of fruit fly development.
00:12:26.21	And so these are some images of just what a developing embryo of Drosophila looks like
00:12:32.09	that has mutations in Toll receptors and you can see a normal one in panel A, up on the left,
00:12:39.29	showing what a normal embryo should look like at this stage,
00:12:42.22	and here down in the lower right, you can see a mutant embryo that is not able to form
00:12:47.20	because it's absent of this Toll receptor.
00:12:50.26	But by performing genetic tricks, you can actually get these embryos to form real flies
00:12:56.26	and these real flies are defective in Toll receptors and what you see when those real flies grow up
00:13:02.07	is something like this.
00:13:03.13	So, here, you have a Drosophila blown up at a very high magnification using something called a scanning electron microscope,
00:13:12.25	and Drosophila don't normally have hair, or beards, in quite this way,
00:13:18.21	what you're looking at here is a very serious fungal infection that this fruit fly could not fend off against
00:13:29.29	because the fly is defective in one of these Toll receptors.
00:13:34.16	This is one of the earliest indications that Toll receptors are important in fly
00:13:41.10	for being able to protect them against fungal infections, and indeed, as it turns out, other infections as well.
00:13:47.02	Turns out that Toll receptors, this is just a molecular diagram of what they look like,
00:13:51.20	the details are not important, these are the ones that are found in fly,
00:13:55.14	which is D. melanogaster is Drosophila melanogaster;
00:14:00.02	these are the similar ones that are found in human.
00:14:01.27	And as soon as they were found, just by scanning the genome,
00:14:05.24	it became very, very clear that maybe they were performing a very similar type of function,
00:14:13.20	and in fact, a series of laboratory studies over the years, all fairly recent, by the way,
00:14:18.17	has really illustrated that these Toll-like receptors that one finds in humans and mice and dogs and cats
00:14:26.04	and everything else, really perform not so much of an important function in development,
00:14:32.12	of the human embryo or fetus, but rather in protecting the human adult,
00:14:39.10	and in fact all animals, against bacteria and indeed, all sorts of pathogens.
00:14:44.09	How, again, by serving as the sensor that macrophages and other similar cells in the immune system use
00:14:50.29	in order to detect when a bacterium is present and in order to allow those cells to know when to activate the immune response,
00:14:59.13	the innate immune response, and when to activate inflammation.
00:15:04.13	Now, again, the way these work is that there are many, many different types of Toll receptors,
00:15:09.13	maybe as many as 14 of them now, and they as a consequence of being so many,
00:15:14.22	they really can bracket the entire universe of different types of pathogens and bacteria.
00:15:19.17	I'm showing here a bacterium is releasing a portion of its cell wall,
00:15:24.16	which it can't avoid doing, and there's specific Toll-like receptors that can actually detect those components,
00:15:30.16	things with names like LPS, or lipopolysaccharide.
00:15:34.03	So, these activate the receptors, which then turn on a typical signaling cascade,
00:15:39.14	again, the details of this are not important, but I just wanted to indicate that something that happens outside the cell
00:15:46.00	stimulates a Toll-like receptor, that then generates an event that occurs inside the cell
00:15:51.20	that basically then licenses the cell, in this case a macrophage, to start the inflammatory process
00:15:57.12	and start protection.
00:15:59.06	Now, here what you're looking at is macrophages in action.
00:16:02.07	These are cells that detect bacteria; actually, what they're detecting is a small yeast particle,
00:16:08.17	such as there, and what you can see very quickly, that macrophage, as soon as I pointed at it,
00:16:12.25	came and ate it. The reason it was able to do that was because there are molecules that yeast make,
00:16:19.25	like bacteria, that can bind to specific Toll-like receptors present on the macrophage
00:16:24.25	and track the macrophage towards, in this case, the yeast particle,
00:16:28.21	and then the macrophage both eats and kills the yeast particle at the same time.
00:16:34.02	Now, what you're not seeing in that movie is that the macrophage also was releasing all sorts of cytokines
00:16:40.20	that would stimulate the surrounding macrophages,
00:16:43.18	but nevertheless, it's a pretty clear indication of exactly what happens.
00:16:47.08	I'd like to show you one more video of just what this process looks like in a bit more resolution.
00:16:52.17	So, here you're looking at 3 macrophages that have been stained with fluorescent dyes,
00:16:57.09	the green dye stains the surface of the plasma membrane with the macrophage
00:17:01.05	and the red dye stains these intracellular digestive elements,
00:17:04.23	exactly the same ones the Metchnikoff colored red in his early diagrams,
00:17:08.06	a hundred or so years earlier.
00:17:10.02	These are the lysozomes, which are responsible for both killing and digesting the bacteria that are being eaten.
00:17:17.09	So, the cell on your left, you can see this little crescent shaped thing there,
00:17:21.21	that's where a particle has bound and I just want you to watch what happens
00:17:27.11	when that particle is internalized, you'll see it first surrounded by green,
00:17:31.28	then rapidly, the green turns red.
00:17:34.08	So, what that means is the bacterium is eaten in a piece of membrane that is derived from the cell surface of the macrophage
00:17:42.12	and that intracellular vacuole then fuses, physically, coalesces with these lysozomes,
00:17:49.23	exposing the internalized bacterium to the cytotoxic and digestive enzymes that are found within the lysozomes
00:17:56.16	that are responsible for killing the internalized bacteria.
00:17:59.06	Ok, just to summarize: innate immunity, discovered by Ellie Metchnikoff, he got a Nobel prize for this work in 1908,
00:18:06.18	and what innate immunity does, is to, remember, to recognize shared pathogen derived components
00:18:13.00	that are recognized by Toll-like receptors, and related receptors, but the most important ones for today are Toll-like receptors.
00:18:19.15	The main cell of the innate immune system are phagocytes,
00:18:24.08	are the cells that eat the bacteria that are recognized.
00:18:27.24	These are cells such as macrophages, and another cell type closely related that we didn't talk about, called neutrophils.
00:18:33.18	These are the cells that are the main effectors, as we say, of the innate immune response
00:18:38.17	by protecting us against bacteria and other types of organisms by eating them and killing them.
00:18:45.11	Ok, so let's go on to the next system.
00:18:48.25	This is adaptive immunity, or the adaptive immune system, which was really discovered about the same time
00:18:55.16	as Metchnikoff discovered the innate immune system.
00:18:58.11	The individual really responsible for this was Paul Ehrlich, who also won a Nobel prize for his work, together with Metchnikoff, in 1908.
00:19:06.15	Here he is in his office. And what Ehrlich found was that when you immunize people
00:19:13.25	with foreign proteins, such as a bacterial toxin, or a protein from a cow or a sheep,
00:19:19.06	those individuals make what Ehrlich called protective antibodies in the blood.
00:19:25.01	And you could actually confer protection from individual to the next.
00:19:29.12	These antibodies were very specific to the individual pathogen or the individual protein that was added
00:19:36.22	and, unlike the innate immune system, you just, any protein wouldn't do, but had to be a very specific protein
00:19:46.00	that would be recognized by a different antibody
00:19:48.23	and finally, also, in this realm, although this really was beyond what Ehrlich himself did,
00:19:55.04	it turns out that the antibodies are not made by the macrophages,
00:20:00.05	but they're rather made by antigen specific lymphocytes,
00:20:03.19	which were the other major cell type that I told you about at the very beginning that really comprise the immune system.
00:20:08.17	So, lymphocytes figure out how to make antibodies against these individual proteins,
00:20:14.01	against these individual pathogens, and use those antibodies to help kill the infected cells.
00:20:20.02	Now this is what an antibody molecule looks like in a 3-dimensional structure.
00:20:24.18	It really consists of two major parts:
00:20:26.07	on top, you can see the so called Fab region and on the bottom you can see the Fc region.
00:20:32.00	Now, both have different functions, the Fab region, which actually consists of two arms,
00:20:37.06	is really where the specificity lies in antibody molecules, so it's this portion of the antibody
00:20:44.21	that is capable of recognizing and binding to any one of the thousands, if not millions,
00:20:50.29	of different proteins that are pathogen derived that can come into our bloodstream at a moment's notice
00:20:58.08	as a consequence of breathing in the wrong stuff or cutting ourselves in the presence of the wrong bacteria.
00:21:04.02	Now, this is just a diagram of what this looks like,
00:21:07.26	again, on the top, you can see these Fab domains, or Fab regions,
00:21:11.29	which are responsible for the specificity of the antibodies
00:21:16.03	and the Fc regions, which have a different function that we'll come to just in a moment.
00:21:21.04	And I think it's important to understand this a bit.
00:21:23.29	This illustrates what the different functions of the Fab and Fc regions are.
00:21:28.16	So, here, in green, is a bacterium. It's being recognized by an antibody that's specific to a protein on that bacterium
00:21:36.05	and you can see here we've drawn that the Fab regions are up, attached to the bacteria,
00:21:42.00	because it's the Fab regions that are responsible for understanding and decoding the specificity in the process.
00:21:48.14	The Fc regions are waving off in the breeze, but they have a very specific function.
00:21:52.15	The first instance they'll recruit another protein that one finds in the blood,
00:21:55.27	called complement. What complement does is basically bind to the Fc portion of an antibody molecule
00:22:02.01	and stick a hole in the surface of the bacteria.
00:22:06.08	It's very hard to live, if you're a cell, if you've got holes stuck in you,
00:22:10.13	so as a consequence, this is one way in which antibody molecules all by themselves can help kill bacteria.
00:22:17.07	Another thing that can happen though is that these antibodies can work in conjunction with Metchnikoff's macrophages
00:22:25.02	so that the Fc regions, that fixed complement to put holes in bacteria
00:22:31.03	also will bind to specific receptors that are present on the surface of macrophages and related cells, called Fc receptors,
00:22:38.22	and these Fc receptors have two functions.
00:22:42.24	One is that they will help mediate the uptake of the bacteria by this process of phagocytosis
00:22:48.13	that I've already shown you in the two videos that we looked at,
00:22:51.09	but also, like Toll receptors, binding of bacteria that are coated with antibody to these Fc receptors
00:22:58.18	will also help aid the process of inflammation by enabling the macrophage and related cells
00:23:04.15	to secrete the hormones and the inflammatory cytokines and other components
00:23:10.00	that will basically indicate to the rest of the immune system that an infection is taking place
00:23:14.24	and help is needed at the site where the macrophages detected these bacteria.
00:23:19.28	Where do antibodies come from? As I already mentioned, they come from lymphocytes,
00:23:24.12	but they come from a very specific lymphocyte, which is called the B-lymphocyte,
00:23:28.22	or more simply, B-cell.
00:23:30.13	These are cells that have the capacity to be able to actually molecularly generate
00:23:37.11	this incredibly broad specificity array of antibodies that one finds,
00:23:44.12	and in fact, that one needs, in order to maintain proper immunity in the blood stream.
00:23:48.29	B-cells will continuously mutate the genes that encode for antibodies
00:23:55.15	and these are called immunoglobulin genes and as a consequence of this continuous process of mutation
00:24:00.17	which is very, very carefully controlled, B-cells can generate the type of diversity that they need,
00:24:06.25	in terms of recognition, to be able to provide and secrete antibodies, or release antibodies,
00:24:13.05	that can interact with virtually any type of pathogen that we are exposed to in life.
00:24:19.16	Now, although B-cells can make antibodies on their own, it turns out, of course, the system is more complicated than that
00:24:26.26	because the best antibodies that B-cells can make
00:24:29.06	are only made are only made when they are, as we say, "helped"
00:24:32.12	by a second major type of lymphocyte and these are called the T-cell.
00:24:36.15	So, T-cells interact with B-cells, while B-cells are interacting with the specific proteins derived from a given pathogen
00:24:45.07	and help the B-cells do a better job making even better antibodies than they could possibly have done on their own.
00:24:52.02	Now, how do they do this?
00:24:54.10	Well, turns out that T-cells have their own receptor, they don't make antibodies,
00:24:58.24	in fact, they make nothing that will go into the bloodstream and directly kill a pathogen like this,
00:25:04.27	under normal circumstances, but they will see another, a little bit of the pathogen,
00:25:10.22	or the pathogenic protein that's come in and use another receptor,
00:25:14.03	which not surprisingly is called the T-cell receptor to recognize that small bit,
00:25:19.14	and then, as a consequence of that, release its own hormones that then help the B-cell do its job
00:25:25.03	at making antibodies. This just shows this process in a little bit more clear fashion, I think,
00:25:30.27	so you see over here, the antigen, or the bacterium coming in,
00:25:34.25	it binding to a receptor on B-cells, which is actually antibody molecule that's embedded in the B-cell.
00:25:40.28	A small piece of that antigen is broken off and put on another receptor
00:25:46.00	on the surface of the B-cell, which interacts with this so-called T-cell receptor
00:25:50.03	that then turns on the T-cells, allowing these hormones, or cytokines, to be secreted by the T-cell,
00:25:56.03	basically telling the B-cell what to do, or at least to do its job better.
00:25:59.16	Finally, I'd just like to address the problem of where do T-cells come from?
00:26:03.19	And how do they know what to do?
00:26:05.19	Turns out, of course, that T-cells come in multiple components, or multiple types.
00:26:11.00	The two basic flavors of T-cell are called CD4 and CD8.
00:26:16.21	It's not really important to be able to distinguish between the two.
00:26:20.04	One of them, the CD4 T-cell, is actually the one that's actually responsible for helping B-cells,
00:26:25.18	CD8 T-cells, which we won't talk about today, have an additional property to that,
00:26:30.15	which is that they can actually kill stuff on their own
00:26:33.00	and form a very important component of anti-viral immunity.
00:26:37.18	But we can take that up another time.
00:26:39.14	Now, the way that T-cells develop their own ability to recognize these small pieces
00:26:46.05	of antigen that are derived from various bacteria or other pathogens,
00:26:51.00	is not because they interact with the B-cells, necessarily,
00:26:54.25	but because they interact with another cell type which I mentioned early on called the dendritic cell.
00:27:00.25	Dendritic cells have the special property of being able to also take up bacteria
00:27:06.12	and they don't really kill the bacteria, they analyze the bacteria.
00:27:10.20	And they ask, what type of bacterium it is, and then display small bits of that bacterium on their surfaces,
00:27:19.02	on molecules here that are called MHC class I or class II molecules
00:27:23.20	that have the very, very special property of being able to detect the appropriate recognition sequences on T-cells
00:27:33.24	such that the right T-cells are generated for the right type of bacterial infection that's taking place.
00:27:41.05	Now, the way this actually works is shown in this little cartoon,
00:27:44.12	and so, once again, you maybe can understand it a little bit better.
00:27:48.27	In the left, you see a happy dendritic cell taking up a not-so happy bacteria.
00:27:55.20	Parts of that bacteria are then generated as a consequence of the dendritic cell
00:28:00.27	having the ability to break it down, placing some parts of, small little bits of the bacterium
00:28:06.09	on the surface, small peptides derived from bacterial proteins, for those of you who know what a peptide is,
00:28:11.15	bound to these MHC class I or class II molecules.
00:28:15.11	T-cells will recognize this, the dendritic cell will make additional cytokines
00:28:21.14	and that T-cell, if it sees its right little bit, it becomes activated,
00:28:26.17	very happy, as you can see here and then runs off to find B-cells that it can help in the antibody generation process.
00:28:35.01	So, it's all a nicely closed loop.
00:28:37.13	I would like to show you a video that tries to put all of this together.
00:28:40.21	So, here you're looking at an animation of someone who's just gotten a sore throat,
00:28:44.18	so you can see the sore throat.
00:28:46.12	What happens in a sore throat, of course, is you have, in most cases, a bacterial infection.
00:28:52.21	So, here, you see a bunch of green bacteria that are colonizing, that have infected the throat
00:28:57.26	and are colonizing the surface of it.
00:29:00.04	Now, those bacteria are covered with specific proteins and that's what's shown in green
00:29:06.02	and the proteins then are sloughed off, or released from the bacteria,
00:29:11.03	and enter the circulation and then also enter into the lymphatics.
00:29:18.20	So, these, remember, are these small conduits that cells in the immune system travel through
00:29:24.18	in order to go from the peripheral tissues into lymph nodes.
00:29:27.27	So, cells of the immune system, such as dendritic cells,
00:29:31.02	have taken up these proteins, B-cells have taken up these proteins,
00:29:35.27	and then come back to these central congregating sites that are connected to all of these lymphatic vessels
00:29:42.21	called lymph nodes. We talked about these in the very beginning.
00:29:46.17	So, here, you see, in this particular video, not the cells, but the bacterial protein entering into the lymph nodes,
00:29:52.23	where it encounters all of these lymphocytes and dendritic cells
00:29:56.17	that begin to take up the bacterial protein
00:29:59.09	and whatever bacteria that come in and begin to interrogate what has happened,
00:30:04.23	respond via Toll-like receptors to these proteins and other components and start to be activated.
00:30:12.09	So here you see, now, a blow-up of the surface of the B-cell,
00:30:15.21	these are the receptors on the surface of the B-cell, this one seems to be specific for this particular bacterial protein
00:30:22.07	because you can see as these proteins come down,
00:30:26.00	they bind to these receptors, one and then a second and a third and a fourth.
00:30:31.12	And as a consequence of all of these receptors accumulating together, particularly if a T-cell is around,
00:30:37.12	these B-cells will then generate a signal, as you can see here,
00:30:43.01	that then tells the B-cell it has recognized the right antigen, the one that it was born to recognize,
00:30:50.05	and it basically gets activated and as a consequence of getting activated,
00:30:56.11	it not only starts moving, but as you'll see in a second, it starts to grow.
00:31:01.14	There, it's dividing two and four and eight, 16, et cetera, et cetera,
00:31:06.13	you wind up with a clone of B-cells, in other words, they're all identical to the first one,
00:31:11.17	they just expand, make more and more of themselves,
00:31:14.18	and the reason for that is so that the immune system can then generate a large amount of the antibody
00:31:21.01	that it already had that can then neutralize the bacteria.
00:31:26.20	So, here you see these B-cells after they've grown up, and replicated themselves,
00:31:30.23	now secreting large quantities of these antibodies that enter not only back into the lymphatics,
00:31:38.07	but now also permeate into the blood stream and can circulate throughout the body,
00:31:43.00	including going back to the original bacteria that had colonized the throat,
00:31:48.29	creating the sore throat in the first place, binding to it, complement will fix to it at that point,
00:31:55.14	and here, in this last image, a macrophage or something similar to that is coming in
00:32:01.02	and as a consequence of recognizing the antibody bound to the bacterium,
00:32:04.16	being attracted by the bacterium itself, you can see this macrophage eating these cells and kill them.
00:32:10.12	And eventually, we get better, as a consequence of all this.
00:32:15.17	Ok, just one last word just to make sure that you at least get the basic concept
00:32:22.01	of how the immune system works, what its logic is, what its function is.
00:32:26.12	I want you to remember that the immune system consists of two basic components:
00:32:30.25	the innate immune system, discovered by Metchnikoff, and the adaptive immune system, discovered by Ehrlich.
00:32:36.02	The innate immune system exists and it’s a very primitive form of the immune response.
00:32:41.04	It exists to recognize components that are found on virtually all pathogens,
00:32:46.21	without really distinguishing so well one pathogen from the next.
00:32:49.27	The adaptive immune system, on the other hand, is highly specific
00:32:53.07	and makes antibodies through the activity of T-cells and B-cells that can specifically identify very, very highly individual pathogens
00:33:02.01	and very highly individual viruses and help, working together with the innate immune system,
00:33:09.00	killing them off.
00:33:10.08	Now, as I mentioned, one of the big problems that we've had until fairly recently,
00:33:16.22	just really within the last 15 years or so is really understanding
00:33:20.17	how the innate and the adaptive immune system work together.
00:33:23.28	In fact, Metchnikoff or Ehrlich didn't really understand this either
00:33:27.13	but this is a realization that was achieved by another scientist, just in 2011,
00:33:36.23	received a Nobel prize, tragically died just days before learning of the award,
00:33:42.10	this is Ralph Steinman, who worked at the Rockefeller University in New York,
00:33:47.23	and Ralph was really the person who is responsible for our understanding that dendritic cells exist
00:33:54.01	and that dendritic cells provide this missing link.
00:33:56.27	They are like macrophages in the sense that they have all of the Toll-like receptors macrophages have,
00:34:01.08	they have the capacity of taking up bacteria and other pathogens,
00:34:04.10	and to some extent killing them.
00:34:06.29	But that's not really what their major role in the immune system is.
00:34:10.11	What their role is is to carry the information, small pieces of the bacteria that are preserved on the surface of the dendritic cell,
00:34:18.03	they take that information from the periphery, where the dendritic cell first encountered the bacterium,
00:34:25.21	into lymph nodes and into the lymphoid organs,
00:34:28.14	basically instructing the cells of the adaptive immune response, the B-cells and the T-cells,
00:34:34.01	as to exactly what type of bacterium is present,
00:34:37.12	stimulating their activities, stimulating their growth, and ultimately leading to the protective antibody responses
00:34:44.22	that you saw in the video.
00:34:46.18	Ok, I hope you enjoy understanding something about the immune system
00:34:52.21	because it really is very important and there are a lot of resources,
00:34:56.12	both online and in print, that you can go to in order to be able to learn more
00:35:00.21	and test your own knowledge of this very, very important and very elemental part of biology.
00:35:06.09	Thank you.