Understanding T-Cell Development Process

All right Ninjas, what we're going to do in this video is we're going to talk about T-cell development. All right, before we do that, let's understand where is the actual T-cells being made. Okay, so if we look here in this diagram, just give you kind of a look at the anatomical structures here. We're going to have our red bone marrow here where the actual T-cells are being produced. And then we're going to have our blood vessel, which is going to be our sinusoidal capillaries that they can be pushed into. But then we're going to take this, what's going to happen is we're going to follow this T-cell. Over here into this blue structure right here, which is called the thymus gland, right? And then we got the thymus gland specifically, we'll talk about this in just a second actually, we'll come back to this. But again, what we're going to need to know is that the T cells are produced within the red bone marrow and then what's going to happen is they're going to have to get sent to a primary lymphoid organ, which is called the thymus gland, where they're going to be able to mature and undergo specific types of selective processes, which we'll explain in detail. Alright, so let's go ahead and dive right into this, right? So we have here in the red bone marrow, If you remember, we had that lymphoid stem cell and when it went over to all these different types of divisions that produced your B cells and your T cells. Let's follow our T cells out of here. So let's say right here I have this T cell right here. So this is our T cell, but it's going to be kind of like a precursor. So this is our T cell, but it's like a precursor T cell. So it's not completely mature yet. It's not at the point where we can actually put that thing into specific secondary lymphoid organs. And we'll talk about that. So what happens is this T cell, it's going to get put into the bloodstream. But how does it know to go to the thymus gland? That's what's going to be cool. So if we come over to the thymus gland for a second. So here again, this is our thymus gland. And where would we find the thymus gland? The thymus gland is actually located, it overlies the heart. So it's located within this mediastinum, right? Which is like a cavity that's located within the thoracic cavity, right? And it houses the esophagus, it houses the heart. it houses the trachea and the other different types of structures right so again this is going to be located within the mediastinum and it overlies the heart now the stymus gland is what's called a primary lymphoid organ that's a primary lymphoid organ what does that mean so this is the one that's actually gonna allow for T cells to develop completely the other primary lymphoid organ is the red bone marrow that's where the B cells develop right okay So this primary lymphoid organ, it's primarily going to be functioning during the younger ages of life. So during the infancy and during the childhood and up to early adolescence, right? But once we hit to the early ages of adolescence, the thymus gland activities begins to decline, and then it starts to atrophy, and then it just becomes filled with fibrous tissue and becomes pretty much non-functional. So again, remember that the thymus gland is specifically functional at young ages. like during infancy and childhood and early adolescence, but as you start to get older, it atrophies, means it's getting smaller, and then on top of that it gets filled with fibrous tissue and actually becomes non-functional. So let's see, what does the thymus gland do that kind of draws these T-cells over to him so that they can undergo specific types of selection and maturation? It secretes specific types of chemokines, right? So these chemotactic agents. What are these chemotactic agents? that it's secreting that are drawing these T cells into this area. These chemotactic agents, there's a couple of them. One is actually going to be called thymocin. Another one can be called thymotaxin. Another one can be called thymopoietin. And then there's other ones because thymopoietin you actually, you know specifically, actually we shouldn't put thymopoietin because thymopoietin, no. Yeah, we can put thymopoietin, I'm sorry, I was thinking about thrombopoietin, but thymopoietin specifically, he also helps to be able to draw these T-cells to the thymus gland. Another one that's really, really important is just generalized thymic factors. Okay, so what are these chemicals right here? These chemicals are acting to be able to draw this T-cell towards the thymus gland. So they're initiating what's called this chemo. haxuses if you will right so this chemo tax is trying to draw this t-cell precursor into the thymus gland so now this t-cell is actually gonna start tracking its way to the thymus gland so now that it's to get received the stimulus from these certain chemicals it's now gonna start moving its way where towards the thymus gland where it's gonna undergo specific maturation processes okay so now now that we know exactly what's happening with this t-cell and how it's getting to the thymus To mature, now we can go ahead and zoom in and see exactly what's happening at the molecular and cellular level. Okay? Okay. So if you look here guys, we have our thymus gland and we're just really, really zoomed in on it now. Okay, so we have our thymus gland here, which again is a primary lymphoid organ. And then if you look over here, I just basically have the spleen, okay, which is a secondary lymphoid organ, and a lymph node, which is another secondary lymphoid organ. Let's go ahead and start right here and work our way towards the left, going with each type of event. All right, so we have our T-cell right here, right? Now, this T-cell... It has its DNA and it's basically, it's a T cell. It hasn't undergone any different, no mechanisms have been acted on upon it yet, right? So it has, it doesn't really have any different types of receptors on it. And I'll explain what those receptors are, those proteins. But what happens is if you remember those chemicals that the thymic cells were secreting, so here's our thymic cell, this is a thymic cell, or an epithelial cell within the thymus, right? It's secreting those chemicals if you remember them. Again, thymocin, thymopoietin, thymic factors. So many, many different types of chemicals. What is that doing? That's acting on this T cell. So when it acts on this T cell, it stimulates the T cell's genes, a specific set of genes, though. And these genes produce a very, very, very important product. And these enzymes that they're actually produced are called RAG1 and RAG2. Why did I mention these? All right, here's why. When these genes... get activated and they produce these proteins called recombinases, so RAG1 and RAG2. What recombinases do is they basically shuffle the DNA. So when they shuffle that DNA they produce different types of proteins for different types of antigens. So what is it going to produce on its actual surface? So these RAG1s and RAG2s are going to act on specific genes, shuffle the DNA and lead to the production of a specific protein which is called a TCR. So this is called a TCR, which stands for T-cell receptor. Now, why did I mention this RAG1 or RAG2? What's the specificity of it? If I have an antigen here, some type of foreign antigen, and it's circular. If I have some type of antigen and it's a square antigen or a triangular antigen, and this is foreign, this TCR that we're making has to be able to recognize any of these foreign antigens. So the recombinases might activate and shuffle the genes to produce a TCR that fits this. circular antigen. Then it might make a TCR to fit this square antigen. And then it might make a TCR to fit this triangular antigen, right? But all of these TCRs are different from one another and unique, and that's because of these recombinase enzymes. All right, that's enough about that. These chemicals are also activating other genes. And these genes are, let's say that we have another line coming down here, activating another set of genes. And these genes are producing what's called CD proteins, or cluster differentiation proteins. So let's draw one here in black. Let's say this protein right here is actually going to be CD. Let's say this is CD8. So cluster differentiation 8. And let's say that this red protein right here that we're going to draw is going to be another cluster differentiation protein, but this one's called CD4. So what's happened here? In this first step here, this is where most of the stuff is actually occurring. These chemicals, thymocin, thymopleten, thymic factors are stimulating this T cell precursor to make TCRs, but different types because of the RAG1 and RAG2. CD8 molecules and CD4 molecules. Now this T cell comes over here. Look at it. It's such a beautiful thing, right? This whole process is unbelievable how all these things happen. But again, what will this guy have on his membrane? He'll have a CD8. He'll have a CD4. And I'll mention why these proteins are really significant. So it has a CD4 and then it also has a TCR. Looks like a bunny. Alright? So now, this thymic cell is going to present some specific types of molecules on its cell membrane. So let's say one of them it presents specifically binds with CD8. Alright? So this molecule binds and only with CD8 and this molecule is called MHC1 okay and CD8 binds with them perfectly it's a good binding it's not too strong but it's just the right type of binding right then CD4, it comes and it perfectly bonds with CD4. And this molecule is called MHC2. And these MHC stands for Major Histocompatibility Complex, type 1 and type 2. These two molecules have recognized and interacted with these MHC molecules. If they do interact with these MHC molecules, that's a good thing. They've positively selected this. So this right here, this event where they recognize them, is called positive selection. Because they recognized, these T cells, recognized the thymic cells MHC1 and MHC2 molecules appropriately. Okay? If it doesn't recognize this, what's going to happen? This cell will undergo apoptosis. Because we need these cells to be able to recognize these MHC1s and MHC2s. So again, if this T cell, its CD8s and its CD4s don't bind with the MHC1 and MHC2, then it'll undergo apoptosis. So again, if this guy does not, if this T cell, if its CD4s and CD8s don't recognize these MHC molecules appropriately and respectively, what's going to happen? It's going to undergo apoptosis. How does that happen? Well, these thymic cells, we're not really concerned with the whole mechanism, but just know that it secretes these specific chemicals. I'll just mention it anyway. It's called FOS. And FOS basically works on... This specific receptor here on the actual T cell and triggers the genes to undergo what activates specific genes to produce apoptosis. Okay, but that's if it does not recognize class 1 and class 2. All right, but he survives. Let's say this guy survives. hooray okay we go to the next step so what's the next step okay now it's this guy's turn now I didn't draw it specifically here but I'm going to show it now so let's say here I draw MHC1 molecule, right? So here's this MHC1 molecule. Same thing from over there. This blue molecule right here that I'm going to draw is still the same thing. It's the MHC2. molecule right now these guys are gonna have always like a self peptide that's a part of these MHC molecules and usually they put it like right here right so let's say it goes specifically right there now this T cell if you remember what did it have I'm going to draw the CD proteins a little bit different now so this red one is going to be CD4 And again, this black one is going to be CD8, which are interacting appropriately with the class 1 and the class 2. But if you remember, what other structure did we have? We had that TCR. Now, the TCRs... Of this T cell, if it recognizes these self-antigens or these self-peptides, that is not a good thing. That means that in the future, these T cells could go and interact with our own tissues, and if it does interact with our own tissues and it causes damage to our tissues, that can lead us to autoimmune disorders. So we don't want that. So in other words, I don't want these TCRs to recognize my own self-peptides or self-antigens. I only want it to recognize foreign things. So what does it do? So again, so for example that one was circular, let's say that this structure right here is like jaggedy. So it's not interacting perfectly right? So that's a good thing. And again let's say that this one was circular right here and this one was jaggedy. And that TCR doesn't fit this self-antigen. It doesn't interact with it. And if it doesn't interact with it, that's a good thing. That's called negative selection. Okay, but if this TCR fits perfectly and binds to that self peptide, that's not a good thing. And that cell will undergo apoptosis. Right. So again, why will it undergo apoptosis? If this T cell has its TCR recognize these self peptides. And again, how will it cause apoptosis? It'll secrete the chemical called FOS and FOS will bind onto a specific receptor and trigger this pathway to lead to apoptosis. So, it's finished such a great thing here. We've gone through how many steps so far? We've gone through the first step, we've gone through the second step, it's got one more thing that has to do before it can finally be a functional T cell. So, it's done all of this test perfectly. It comes to this last point here. And at this last point here, we're going to draw these molecules again. Let's say I have this thymic, let's actually say I have two thymic cells. One here, one down here. And this T cell has a choice. It's got its choice. But really, it's random. So let's say down here, I draw an MHC1 molecule. Okay, so that's my MHC1 molecule. And let's see up here, I draw specifically a MHC2 molecule. If you remember, what's this cell right now? This cell that we had, he is TCR positive, CD4 positive, and CD8 positive. So he has all of these different things that he needs to interact. He comes over here and let's say just by perfectly random chance, I know it seems crazy but just by perfectly random chance, the CD4 molecule on this T cell interacts with the MHC2. So just perfectly, this CD4 molecule here interacts perfectly with the MHC2 molecule. But it doesn't, its CD8 doesn't interact with the class 1. This T cell is going to specifically, what's going to happen is, if it interacts with the class 2, the genes will down regulate. the CD8 molecule. So if you remember here was the CD8. But let's say that this interaction doesn't happen and that this T cell only has a CD4 interact with MHC2. If that reaction only happens, you'll upregulate these CD4 molecules and you'll downregulate these. CD8 molecules. What does down regulate mean? You'll decrease the number of CD8s. What does up regulate mean? You'll increase the number of CD4s. So what would this cell look like, for example? And I'm not going to draw all the CD4s perfectly. I'm just going to draw red markers on this. I'm just going to draw little red dots here. There's a whole bunch of red dots there representing the CD4s and we might have at this point in time maybe one CD8, right? That's it. This cell right here, if it has all of these nice little beautiful CD4s and again what else would it have here? I'm just going to draw these in purple. These TCRs, these T cell receptors. and it down regulates all these CD8s and up regulates all these CD4s. This cell is specifically a T helper cell. Okay? Now, let's say another T cell comes through. So another T cell comes through. And it's by random chance, I know it seems crazy, but by random chance, this CD8 molecule perfectly interacts with the MHC1 molecule. And this interaction between... the CD4 and the MHC2 interaction doesn't occur. This cell will down regulate his CD4 molecule. So in other words, he'll decrease the amount of CD4s and he'll up regulate his CD8s because he interacted with the class 1. So now let's draw this molecule here. So again, what we have all out of on the surface, these CD8 molecules there. And again, he'll start down regulating. He shouldn't have, I'm just showing it for an example. This T helper cell shouldn't have any CD8 molecules. I'm just giving you the idea that it should down regulate the CD8s for this T helper. Same thing with this guy. He shouldn't have any CD4 molecules. I'm showing it to you as an example that these CD4 molecules will be down regulated and completely diminished, right? But again, it'll have a lot of these CD8s and it'll also have a lot of TCRs, right? So this is our TCR, T cell receptor. This cell is specifically called a T-cyto-toxic cell. Okay? One last one, but it's the easiest one. Some of these cells, it's really weird, these cells. Some of these T helper cells can become T regulatory cells and some of these cytotoxic T cells can become T regulatory cells. So I'm gonna draw this right up here then. And what I'm saying here again is that some of these cells, some of the CD4 cells and some of the actual CD8 cells can literally become, so let's say I have two of them over here. They can become T regulatory cells. In these T regulatory cells, again, what can they have on their membrane? They could have CD4 molecules. And what else would they have? TCRs. You have to have the TCRs, these purple molecules right here. But this other cell, he would have CD8 molecules. And these CD8 molecules... as well as TCR molecules. Now I know this seems weird because I just said this was a T helper cell and this was a T cytotoxic cell. Through certain types of cytokines, these actual T helper cells and T cytotoxic T cells can differentiate into a specific type of cell and this is called a T regulatory, sometimes they call them suppressor also, cells. And these are very very important for being able to regulate, prevent these, regulate the activity of the tea helper and the tea cytotoxic to prevent autoimmune diseases. A little piece of it, there is a specific mechanism of how these guys can go into forming tea regulatory. I'm not going to hit too much into it, but they say it's due to certain types of proteins that's present on this guy, like maybe the CD25 and certain chemicals like interleukin 2 that can regulate this activity, but Nonetheless, just know T helper cells and T cytotoxic T cells, some of these guys can get converted into T regulatory. Okay, so we formed all our three cells, all of our three T cells that we need. Now what happens? Now these guys go and get specifically put into different lymphoid organs. What is some of them? Let's just say I draw with one cell here, one cell. It could be any of these. These guys coming right in here. So what are these little black cells right here? These little black cells are called T cells. And they can go to the lymph node and they can park themselves right there in the deep part of the cortex of the lymph node. Where else could they go? They could come in here into the spleen. And in the spleen... what's important is that these T cells literally form right around these red blood vessels that we have drawn right here, these capillaries called sinusoidal capillaries, they come and surround these blood vessels and form what's called peri-arteriolar lymphatic sheaths, or specifically, they just call it. white pulp. They make what's called the white pulp. So again, what can happen, these T cells can go to the lymph nodes and park into the deep part of the cortex or they can surround these specific sinusoidal capillaries and form what's called white pulp or peri-arteriolar lymphatic sheaths. And another place, you see these T regulatory cells? There's a specific place for them. They literally come into this specific area into the thymus gland where they're primarily going to be. This is where a good concentration of them could be, but they can be, again, they could be all over the place too. They could be in the spleen as well as the lymph node. But they've been found to be concentrated in the thymus gland in a specific area which is called the hussars corpuscles or the thymic corpuscles. Okay, so again, in brief, it will undergo, this T cell will undergo positive selection, it'll undergo negative selection, positive meaning it recognizes MHC1 and MHC2. Negative selection meaning it does not recognize the self peptide of the self antigen. Then after that by random chance it'll either get if it CD4 interacts with MHC2 it'll form a CD4 cell or its T helper. If by random chance the CD8 interacts with the MHC1 it'll actually turn into a T cytotoxic and then some of these T helper cells and T cytotoxic T cells can be converted into T regulatory cells maybe through a CD25 interleukin 2 interaction, right? And then these cells, all of these cells can be sent to secondary lymphoid organs like the core deep part of the cortex and lymph node or the white pulp within the spleen or the hasas corpuscles and the thymus. And there's other different areas too besides that. They can go to the tonsils. They can go into the mucosa associated lymphatic tissue, which could be in your respiratory tract, your ureterogenital tract. They can be all over the place, right? But again, know that this is the entire process starting from where? Where do we start? And an overall outlook starting in the red bone marrow. That's where they're made. They're made within the red bone marrow, but they mature in the thymus and then from there, where can they go? They can go to secondary lymphoid organs where they'll carry out their functional processes. All right Ninjners, I hope that helped. Take it easy.

But then we're going to take this, what's going to happen is we're going to follow this T-cell. Over here into this blue structure right here, which is called the thymus gland, right? And then we got the thymus gland specifically, we'll talk about this in just a second actually, we'll come back to this.

But again, what we're going to need to know is that the T cells are produced within the red bone marrow and then what's going to happen is they're going to have to get sent to a primary lymphoid organ, which is called the thymus gland, where they're going to be able to mature and undergo specific types of selective processes, which we'll explain in detail. Alright, so let's go ahead and dive right into this, right? So we have here in the red bone marrow, If you remember, we had that lymphoid stem cell and when it went over to all these different types of divisions that produced your B cells and your T cells. Let's follow our T cells out of here.

So let's say right here I have this T cell right here. So this is our T cell, but it's going to be kind of like a precursor. So this is our T cell, but it's like a precursor T cell.

So it's not completely mature yet. It's not at the point where we can actually put that thing into specific secondary lymphoid organs. And we'll talk about that. So what happens is this T cell, it's going to get put into the bloodstream. But how does it know to go to the thymus gland?

That's what's going to be cool. So if we come over to the thymus gland for a second. So here again, this is our thymus gland. And where would we find the thymus gland?

The thymus gland is actually located, it overlies the heart. So it's located within this mediastinum, right? Which is like a cavity that's located within the thoracic cavity, right? And it houses the esophagus, it houses the heart.

it houses the trachea and the other different types of structures right so again this is going to be located within the mediastinum and it overlies the heart now the stymus gland is what's called a primary lymphoid organ that's a primary lymphoid organ what does that mean so this is the one that's actually gonna allow for T cells to develop completely the other primary lymphoid organ is the red bone marrow that's where the B cells develop right okay So this primary lymphoid organ, it's primarily going to be functioning during the younger ages of life. So during the infancy and during the childhood and up to early adolescence, right? But once we hit to the early ages of adolescence, the thymus gland activities begins to decline, and then it starts to atrophy, and then it just becomes filled with fibrous tissue and becomes pretty much non-functional.

So again, remember that the thymus gland is specifically functional at young ages. like during infancy and childhood and early adolescence, but as you start to get older, it atrophies, means it's getting smaller, and then on top of that it gets filled with fibrous tissue and actually becomes non-functional. So let's see, what does the thymus gland do that kind of draws these T-cells over to him so that they can undergo specific types of selection and maturation? It secretes specific types of chemokines, right? So these chemotactic agents.

What are these chemotactic agents? that it's secreting that are drawing these T cells into this area. These chemotactic agents, there's a couple of them.

One is actually going to be called thymocin. Another one can be called thymotaxin. Another one can be called thymopoietin.

And then there's other ones because thymopoietin you actually, you know specifically, actually we shouldn't put thymopoietin because thymopoietin, no. Yeah, we can put thymopoietin, I'm sorry, I was thinking about thrombopoietin, but thymopoietin specifically, he also helps to be able to draw these T-cells to the thymus gland. Another one that's really, really important is just generalized thymic factors.

Okay, so what are these chemicals right here? These chemicals are acting to be able to draw this T-cell towards the thymus gland. So they're initiating what's called this chemo.

haxuses if you will right so this chemo tax is trying to draw this t-cell precursor into the thymus gland so now this t-cell is actually gonna start tracking its way to the thymus gland so now that it's to get received the stimulus from these certain chemicals it's now gonna start moving its way where towards the thymus gland where it's gonna undergo specific maturation processes okay so now now that we know exactly what's happening with this t-cell and how it's getting to the thymus To mature, now we can go ahead and zoom in and see exactly what's happening at the molecular and cellular level. Okay? Okay.

So if you look here guys, we have our thymus gland and we're just really, really zoomed in on it now. Okay, so we have our thymus gland here, which again is a primary lymphoid organ. And then if you look over here, I just basically have the spleen, okay, which is a secondary lymphoid organ, and a lymph node, which is another secondary lymphoid organ.

Let's go ahead and start right here and work our way towards the left, going with each type of event. All right, so we have our T-cell right here, right? Now, this T-cell...

It has its DNA and it's basically, it's a T cell. It hasn't undergone any different, no mechanisms have been acted on upon it yet, right? So it has, it doesn't really have any different types of receptors on it.

And I'll explain what those receptors are, those proteins. But what happens is if you remember those chemicals that the thymic cells were secreting, so here's our thymic cell, this is a thymic cell, or an epithelial cell within the thymus, right? It's secreting those chemicals if you remember them. Again, thymocin, thymopoietin, thymic factors. So many, many different types of chemicals.

What is that doing? That's acting on this T cell. So when it acts on this T cell, it stimulates the T cell's genes, a specific set of genes, though. And these genes produce a very, very, very important product. And these enzymes that they're actually produced are called RAG1 and RAG2.

Why did I mention these? All right, here's why. When these genes...

get activated and they produce these proteins called recombinases, so RAG1 and RAG2. What recombinases do is they basically shuffle the DNA. So when they shuffle that DNA they produce different types of proteins for different types of antigens.

So what is it going to produce on its actual surface? So these RAG1s and RAG2s are going to act on specific genes, shuffle the DNA and lead to the production of a specific protein which is called a TCR. So this is called a TCR, which stands for T-cell receptor. Now, why did I mention this RAG1 or RAG2?

What's the specificity of it? If I have an antigen here, some type of foreign antigen, and it's circular. If I have some type of antigen and it's a square antigen or a triangular antigen, and this is foreign, this TCR that we're making has to be able to recognize any of these foreign antigens. So the recombinases might activate and shuffle the genes to produce a TCR that fits this.

circular antigen. Then it might make a TCR to fit this square antigen. And then it might make a TCR to fit this triangular antigen, right?

But all of these TCRs are different from one another and unique, and that's because of these recombinase enzymes. All right, that's enough about that. These chemicals are also activating other genes.

And these genes are, let's say that we have another line coming down here, activating another set of genes. And these genes are producing what's called CD proteins, or cluster differentiation proteins. So let's draw one here in black.

Let's say this protein right here is actually going to be CD. Let's say this is CD8. So cluster differentiation 8. And let's say that this red protein right here that we're going to draw is going to be another cluster differentiation protein, but this one's called CD4.

So what's happened here? In this first step here, this is where most of the stuff is actually occurring. These chemicals, thymocin, thymopleten, thymic factors are stimulating this T cell precursor to make TCRs, but different types because of the RAG1 and RAG2. CD8 molecules and CD4 molecules. Now this T cell comes over here.

Look at it. It's such a beautiful thing, right? This whole process is unbelievable how all these things happen. But again, what will this guy have on his membrane?

He'll have a CD8. He'll have a CD4. And I'll mention why these proteins are really significant.

So it has a CD4 and then it also has a TCR. Looks like a bunny. Alright?

So now, this thymic cell is going to present some specific types of molecules on its cell membrane. So let's say one of them it presents specifically binds with CD8. Alright? So this molecule binds and only with CD8 and this molecule is called MHC1 okay and CD8 binds with them perfectly it's a good binding it's not too strong but it's just the right type of binding right then CD4, it comes and it perfectly bonds with CD4.

And this molecule is called MHC2. And these MHC stands for Major Histocompatibility Complex, type 1 and type 2. These two molecules have recognized and interacted with these MHC molecules. If they do interact with these MHC molecules, that's a good thing.

They've positively selected this. So this right here, this event where they recognize them, is called positive selection. Because they recognized, these T cells, recognized the thymic cells MHC1 and MHC2 molecules appropriately.

Okay? If it doesn't recognize this, what's going to happen? This cell will undergo apoptosis. Because we need these cells to be able to recognize these MHC1s and MHC2s.

So again, if this T cell, its CD8s and its CD4s don't bind with the MHC1 and MHC2, then it'll undergo apoptosis. So again, if this guy does not, if this T cell, if its CD4s and CD8s don't recognize these MHC molecules appropriately and respectively, what's going to happen? It's going to undergo apoptosis.

How does that happen? Well, these thymic cells, we're not really concerned with the whole mechanism, but just know that it secretes these specific chemicals. I'll just mention it anyway.

It's called FOS. And FOS basically works on... This specific receptor here on the actual T cell and triggers the genes to undergo what activates specific genes to produce apoptosis.

Okay, but that's if it does not recognize class 1 and class 2. All right, but he survives. Let's say this guy survives. hooray okay we go to the next step so what's the next step okay now it's this guy's turn now I didn't draw it specifically here but I'm going to show it now so let's say here I draw MHC1 molecule, right?

So here's this MHC1 molecule. Same thing from over there. This blue molecule right here that I'm going to draw is still the same thing.

It's the MHC2. molecule right now these guys are gonna have always like a self peptide that's a part of these MHC molecules and usually they put it like right here right so let's say it goes specifically right there now this T cell if you remember what did it have I'm going to draw the CD proteins a little bit different now so this red one is going to be CD4 And again, this black one is going to be CD8, which are interacting appropriately with the class 1 and the class 2. But if you remember, what other structure did we have? We had that TCR.

Now, the TCRs... Of this T cell, if it recognizes these self-antigens or these self-peptides, that is not a good thing. That means that in the future, these T cells could go and interact with our own tissues, and if it does interact with our own tissues and it causes damage to our tissues, that can lead us to autoimmune disorders.

So we don't want that. So in other words, I don't want these TCRs to recognize my own self-peptides or self-antigens. I only want it to recognize foreign things. So what does it do?

So again, so for example that one was circular, let's say that this structure right here is like jaggedy. So it's not interacting perfectly right? So that's a good thing. And again let's say that this one was circular right here and this one was jaggedy. And that TCR doesn't fit this self-antigen.

It doesn't interact with it. And if it doesn't interact with it, that's a good thing. That's called negative selection. Okay, but if this TCR fits perfectly and binds to that self peptide, that's not a good thing.

And that cell will undergo apoptosis. Right. So again, why will it undergo apoptosis? If this T cell has its TCR recognize these self peptides. And again, how will it cause apoptosis?

It'll secrete the chemical called FOS and FOS will bind onto a specific receptor and trigger this pathway to lead to apoptosis. So, it's finished such a great thing here. We've gone through how many steps so far? We've gone through the first step, we've gone through the second step, it's got one more thing that has to do before it can finally be a functional T cell. So, it's done all of this test perfectly.

It comes to this last point here. And at this last point here, we're going to draw these molecules again. Let's say I have this thymic, let's actually say I have two thymic cells. One here, one down here.

And this T cell has a choice. It's got its choice. But really, it's random. So let's say down here, I draw an MHC1 molecule. Okay, so that's my MHC1 molecule.

And let's see up here, I draw specifically a MHC2 molecule. If you remember, what's this cell right now? This cell that we had, he is TCR positive, CD4 positive, and CD8 positive. So he has all of these different things that he needs to interact. He comes over here and let's say just by perfectly random chance, I know it seems crazy but just by perfectly random chance, the CD4 molecule on this T cell interacts with the MHC2.

So just perfectly, this CD4 molecule here interacts perfectly with the MHC2 molecule. But it doesn't, its CD8 doesn't interact with the class 1. This T cell is going to specifically, what's going to happen is, if it interacts with the class 2, the genes will down regulate. the CD8 molecule.

So if you remember here was the CD8. But let's say that this interaction doesn't happen and that this T cell only has a CD4 interact with MHC2. If that reaction only happens, you'll upregulate these CD4 molecules and you'll downregulate these.

CD8 molecules. What does down regulate mean? You'll decrease the number of CD8s. What does up regulate mean? You'll increase the number of CD4s.

So what would this cell look like, for example? And I'm not going to draw all the CD4s perfectly. I'm just going to draw red markers on this.

I'm just going to draw little red dots here. There's a whole bunch of red dots there representing the CD4s and we might have at this point in time maybe one CD8, right? That's it. This cell right here, if it has all of these nice little beautiful CD4s and again what else would it have here? I'm just going to draw these in purple.

These TCRs, these T cell receptors. and it down regulates all these CD8s and up regulates all these CD4s. This cell is specifically a T helper cell. Okay? Now, let's say another T cell comes through.

So another T cell comes through. And it's by random chance, I know it seems crazy, but by random chance, this CD8 molecule perfectly interacts with the MHC1 molecule. And this interaction between...

the CD4 and the MHC2 interaction doesn't occur. This cell will down regulate his CD4 molecule. So in other words, he'll decrease the amount of CD4s and he'll up regulate his CD8s because he interacted with the class 1. So now let's draw this molecule here. So again, what we have all out of on the surface, these CD8 molecules there.

And again, he'll start down regulating. He shouldn't have, I'm just showing it for an example. This T helper cell shouldn't have any CD8 molecules.

I'm just giving you the idea that it should down regulate the CD8s for this T helper. Same thing with this guy. He shouldn't have any CD4 molecules.

I'm showing it to you as an example that these CD4 molecules will be down regulated and completely diminished, right? But again, it'll have a lot of these CD8s and it'll also have a lot of TCRs, right? So this is our TCR, T cell receptor.

This cell is specifically called a T-cyto-toxic cell. Okay? One last one, but it's the easiest one.

Some of these cells, it's really weird, these cells. Some of these T helper cells can become T regulatory cells and some of these cytotoxic T cells can become T regulatory cells. So I'm gonna draw this right up here then. And what I'm saying here again is that some of these cells, some of the CD4 cells and some of the actual CD8 cells can literally become, so let's say I have two of them over here.

They can become T regulatory cells. In these T regulatory cells, again, what can they have on their membrane? They could have CD4 molecules. And what else would they have? TCRs.

You have to have the TCRs, these purple molecules right here. But this other cell, he would have CD8 molecules. And these CD8 molecules... as well as TCR molecules. Now I know this seems weird because I just said this was a T helper cell and this was a T cytotoxic cell.

Through certain types of cytokines, these actual T helper cells and T cytotoxic T cells can differentiate into a specific type of cell and this is called a T regulatory, sometimes they call them suppressor also, cells. And these are very very important for being able to regulate, prevent these, regulate the activity of the tea helper and the tea cytotoxic to prevent autoimmune diseases. A little piece of it, there is a specific mechanism of how these guys can go into forming tea regulatory. I'm not going to hit too much into it, but they say it's due to certain types of proteins that's present on this guy, like maybe the CD25 and certain chemicals like interleukin 2 that can regulate this activity, but Nonetheless, just know T helper cells and T cytotoxic T cells, some of these guys can get converted into T regulatory.

Okay, so we formed all our three cells, all of our three T cells that we need. Now what happens? Now these guys go and get specifically put into different lymphoid organs.

What is some of them? Let's just say I draw with one cell here, one cell. It could be any of these.

These guys coming right in here. So what are these little black cells right here? These little black cells are called T cells.

And they can go to the lymph node and they can park themselves right there in the deep part of the cortex of the lymph node. Where else could they go? They could come in here into the spleen.

And in the spleen... what's important is that these T cells literally form right around these red blood vessels that we have drawn right here, these capillaries called sinusoidal capillaries, they come and surround these blood vessels and form what's called peri-arteriolar lymphatic sheaths, or specifically, they just call it. white pulp. They make what's called the white pulp. So again, what can happen, these T cells can go to the lymph nodes and park into the deep part of the cortex or they can surround these specific sinusoidal capillaries and form what's called white pulp or peri-arteriolar lymphatic sheaths.

And another place, you see these T regulatory cells? There's a specific place for them. They literally come into this specific area into the thymus gland where they're primarily going to be.

This is where a good concentration of them could be, but they can be, again, they could be all over the place too. They could be in the spleen as well as the lymph node. But they've been found to be concentrated in the thymus gland in a specific area which is called the hussars corpuscles or the thymic corpuscles.

Okay, so again, in brief, it will undergo, this T cell will undergo positive selection, it'll undergo negative selection, positive meaning it recognizes MHC1 and MHC2. Negative selection meaning it does not recognize the self peptide of the self antigen. Then after that by random chance it'll either get if it CD4 interacts with MHC2 it'll form a CD4 cell or its T helper.

If by random chance the CD8 interacts with the MHC1 it'll actually turn into a T cytotoxic and then some of these T helper cells and T cytotoxic T cells can be converted into T regulatory cells maybe through a CD25 interleukin 2 interaction, right? And then these cells, all of these cells can be sent to secondary lymphoid organs like the core deep part of the cortex and lymph node or the white pulp within the spleen or the hasas corpuscles and the thymus. And there's other different areas too besides that.

They can go to the tonsils. They can go into the mucosa associated lymphatic tissue, which could be in your respiratory tract, your ureterogenital tract. They can be all over the place, right? But again, know that this is the entire process starting from where?

Where do we start? And an overall outlook starting in the red bone marrow. That's where they're made. They're made within the red bone marrow, but they mature in the thymus and then from there, where can they go? They can go to secondary lymphoid organs where they'll carry out their functional processes.

All right Ninjners, I hope that helped. Take it easy.

Transcript for:Understanding T-Cell Development Process

Transcript for:
Understanding T-Cell Development Process