In this section, we're going to look at how you get the antigen ready so that a T cell can identify it. To do that, I'm going to look into my owl my many peptides, and find out what I've got in here. I've got some antigens and I have, oh dear, this is a lipid antigen, we'll look at that later, and I have two different peptide antigens. I have a longer one, and that's going to be for my Th cells, and I have a shorter one, and that's going to be for my Tc cells. But I can't just give them to the Th or Tc cells. The receptor, which I have around here, will not recognize them. Now, they must be presented. So, I can present my short peptide on an MHC I molecule, and I can present my longer peptide on an MHC II molecules. So, you can consider your MHC molecules as, in a sense, some form of mechanical device for making sure your TA cells can recognize the antigens that they're supposed to bind to. So, now let's go back and look at the actual alpha-beta receptor. This is the receptor used by both Tc and Th cells. So, I'm going to pretend that there's one or the other of them down here, and I'm going to nail this thing down like this. So it doesn't move around. Here's your alpha-beta receptor. Now, if this is a Tc cell, the MHC I will bind it in its binding site up here. This is something of a review but we're going to put it in context. So, here is a picture of an MHC I molecule. Actually, this is a foam board model. You can see here is the MHC I. Here is the beta microglobulin that helps to hold it up. Here is the antigen at the top that is held in, it's, again, 8-10 amino acids long and it bows out. So, what we have to do is find a way to pick up antigen, from a source, the protein, we'll see inside the cell, chop it into the right size, and put it onto this molecule. Now, so up here this would be the cell that's displaying this to a Th cell. When it does that, if the Th cell has, excuse me, this is a Tc cell, if the Tc cell has a binding site that recognizes this antigen, it will alert, and it will improve its finding by coming in with a CD8 molecule that will bind to the alpha three section in here, the other end which isn't quite long enough or is too curvy at the moment, will be embedded in the membrane, and this CD8 will stabilize the binding between the MHC I, the Tc cell and the antigen. That will then set off a chain of events in the interior of the cell that will activate the Tc cell and, we'll see, ultimately allow it to attack a cell displaying a foreign antigen. Okay. So, what if you're a Th cell? If you're a Th cell, then you're still going to use that alpha-beta receptor. But you will be designed to respond to antigen that is held on the MHC II molecule. Again, in this case, it's going to be a sort of long floppy piece of protein. It's held in the cleft between the alpha and the beta and we're going to have to chop this up into a different size. We're going to have to load it into in a different place, but we're still in both cases going to put them on the surface of a cell. In this case, the cell is presenting this antigen to the Th cell, and the Th cell will also stabilize that association with a CD4 in this case, that binds between these two, again, and stabilizes the whole relationship. So, take a look at this, and I have also put pictures of these relationships in your outline for you to look at. This is a review of some of the things that we've done before, but you need to bear in mind, as we go through this incredibly long sequence of events for both of these, where we're headed. We're headed to the binding of MHC I to Tc cells. The binding of MHC II to T8 cells and the recognition of the antigen that has been essentially marriaged into the proper size, put in the proper place, and sent down the proper pathway. That's what we're doing next. Here, we have a table from your outline that summarizes the properties of the three major antigen presenting cells. These are the professional antigen presenting cells or APCs, and you can see we have three overall categories, the sentinel dendritic cell, the macrophage and the B cell. These are the guys that do the primary presentation of MHC II with little pieces of antigen on it to the Th cells. Okay. So, we're talking about presentation to Th cells, not display to Tc cells. Now, notice, we're going to go through and look at these things and talk about whether they are resting or active, how they take up the antigen, again, how much MHC II they make generally, whether they make the B7 co-stimulator, and what they will do in terms of activating T cells. So, let's do some general considerations and then go back and do a bit of comparison. First of all, here's a reminder, here's a picture from the early part of part one of this course series. You can see an antigen presenting cell has taken up an antigen, it's hydrolyzed it, it's put it onto MHC II and in this case, it's found a T Cell whose TCR recognizes the antigen and that cell is activating, and of course, what a T cells goes is secretes a bunch of cytokines, which will regulate the immune response. So that's where we're going with this. One thing I wanted to show you was a picture of some langerhan dendritic cells. There are a number of different kinds of dendritic cells. They mostly sit in various peripheral parts of the body. If they take up antigen, they will activate and migrate to a secondary lymphoid organ and look for a Th cell to present to. In this case, these in the skin are langerhan dendritic cells and they're named after the same guy who also named the islets of Langerhans in the pancreas that secrete insulin and glucagon. So, the thing that these two cells have in common, langerhans dendritic and langerhans secretion cells, are that they were found by Langerhans. In those days, you could get your name on all kinds of things, good luck doing that today, we're going to have again other naming conventions that are every bit as hard to make sense of but will not get you your place in history. All right. So here's the cells, they've taken up a specific stain or dye, so you can see them. This is going to be in a category of cells, that is the first thing that can kick off a T cell response to a brand new infection. That is to say, what are the things that we're pretty careful about is that we really try not to activate Th cells unless we're sure there's a danger. That doesn't always work and that's why we have auto-immune diseases, but in this case, this is the only type of cell that is constituentably active. It's always ready to go. It can pick up things by both endocytosis and phagocytosis, that means, small and large particle. It makes MHC all the time, that means its constituentive. It makes B7 all the time and it is the only one that can activate naive T cells from the get-go. So, if you have a brand new infection, this is the cell that can respond to it from day one. Now, later on, we'll see that B cells can also activate naive T cells but not until they themselves have been activated. In this case, we have something that's a little in the sense like an NK cell in that it does not need to be activated by something else before it can go on the alert, and activate a naive T cell or for that matter, any other kind of Th cell. So, this is in a sense at the ground zero of noticing that there's an infection and sending the word out to do something about it. If these cells phagocytize something or endocytize something, decided to danger based on its activation of their toe-like and other receptors, and these cells will pack up and go to a secondary lymphoid organ, will present antigen and try to find a Th cell that has a receptor that recognizes it. Now, sometimes people get confused by the notation that B cells are actually the most effective at gathering up antigen to present it to Th cells. Because I just told you that the sentinel dendritic cell is the only thing that can alert T cells to brand new infections, so it's a bit of a paradox and how do I resolve that? Well, it turns out once a B cell has been activated, because it takes the antigen in by receptor mediated endocytosis, it's capable of picking up antigen like needles out of a stack. That is, if there's any engine in the vicinity, it will stick to the immunoglobulin receptors. So let's just quickly review what happens next as we did in the previous course. So, the B cell will then internalize these receptors and their antigen, it will break it up, it will then fuse with a vesicle containing MHC II, and then it will load the antigen on the MHC II. The MHC II will then, in the vesicle, go to the surface of the cell and display that antigen to a Th cell. So when the Th cell comes in, it's going to be activated by this antigen and eventually that activation is going to cause it to produce the CD40 ligand, which will then activate the B cell. Now, when you activate the B cell, you produce something called B7, and this is what turns around and activates the Th cell by binding the CD28. Once the B cell has been activated and it's making B7, it can then turn around and activate T cells all by itself. So with that in mind, let's go back and look at that table again. Here it is. We have the dendritic cells which are constitutively active in the sense that they are always active. They're ready to go. They have the MHC II and B7 at all times and they can basically up-regulate any form of T cell from naive to active, to a memory T-cell in case some infection is rearing its ugly head for the second or more time. The macrophages on the other hand, there's more of them. They're running around. If there still resting, they don't do too much. But if they're induced by again, an up-regulation of cytokines from T cells that had been activated by say a sentinel dendritic cell. Once they're active then they go into MHC II production, B7 production and they can maintain the response for activating effector cells, and they can also activate memory T cells that may be floating around and needing a little bit of product. So, the macrophages are part of the overall, should I say monitoring of an ongoing infection? The B cells on the other hand, even when they are resting, are very good at picking up antigen. But they have to be activated in order to produce full levels of MHC II. They don't produce B7 until they've been activated. Initially, with the lower levels of MHC II and the beginnings of B7 presentation, they can essentially work with the macrophages to continue to support effector Th cells, and also will a activate a memory cell. But on the other hand, once they're activated, they can activate a naive cell. But, if you want to start at ground zero, new infections first day, that is going to be done by a sentinel dendritic cell and it is basically permissive for the whole response. One of the things it does is again, it produces a bit of control as to whether or not the cell totally begins to respond to an antigen on the off chance it might not be something worthy of spending a lot of energy on or might even be dangerous if it's one of your own self. Now, at this point, then we kind of looked at how the setup works and we're going to look at some other details of more things we know about what does and does not work in terms of T cell activation.