So, now, we're finally getting to T cells. We're going to look at how T cell develop. In this respect, there are many aspects of T cell development that are a lot like a B cell development. So, I am hoping you took part one. If you didn't take part one, the information in the video should still be up there, but there are many aspects that are similar. We're going to rearrange the genes using exactly the same mechanisms, we're going to do many of the same things in terms of negative selection and getting rid of cells that are going to recognize your own body, but there are a few things that are different and you need to keep an eye on that. First of all, T cells do start out as hematopoietic stem cells in the bone marrow. But in order to mature, they have to leave the bone marrow and migrate to the thymus. When they are in the thymus, they're going to go through a really elaborate series of stages of selection, and one of the parts of that will be to make sure that they can recognize the antigen that's presented on either MHC I or MHC II, and we will see we also have the possibility of making Gamma Delta cells. So, when we look at T cell development, we've got a few things that are quirky and a number of things that are similar to what we did before with the B cells. So, with that in mind, let's go launch into the specifics of T cell development. T cells are all about information. They're about receiving information, making internal changes based on information, sending out information to coordinate responses, and receiving feedback on how things are going, and all of this is done with chemical signals. So, let's begin at the beginning and look at some of how those signals work. The first category we're going to look at is transcription factors, and these are proteins that act in the nucleus by binding directly or indirectly to DNA, and determining what genes get turned on or transcribed and how much message gets made. The first one in the series to produce a T cell is something called GATA2, and you need that simply to take a hematopoietic stem cell and send it down the road to differentiation. Here, we have an alpha helix that inserts itself into the major groove, and you can see these things are flopping around, other domains sticking out that recruit more proteins that will help turn this cell on. To become a T cell however, this differentiating cell must turn on ikaros, and ikaros is a transcription factor that will send things down the lymphoid as opposed to the myeloid pathway of development. This is an example of the zinc finger protein, that's what ikaros is. It has these domains the hang on, again, to the major groove of the DNA molecule shown here in dark orange. This particular transcription factor will send the cell down a lymphoid pathway, which means it can be a B cell a T cell or an NK cell. So, clearly, we need some more specific direction to turn into a T cell. The next two signals we're looking at are membrane receptors that receive external signals that keep the T cell heading down the pathway to T cell development. Now, oddly enough, the first one that is the c-Kit receptors, sometimes, called CD117 for its order in membrane identification, receives a paracrine factor that's called steel or sometimes stem cell factor, and the function of this paracrine factor is to prevent the cell from determining or differentiating prematurely. So, this particular signal is found in the T cell progenitors or pre T cells or the thymocytes before they go into the last stages of their differentiation. This receptor is also found in germ cells, is found in pluripotent stem cells, and it's a signal that's used in those situations to prevent the cell from committing prematurely to a particular course of action or development. Unsurprisingly, this receptor will decline during the course of T cell development and it enhances to its final row, this will have been longer. Now, of course, you have to tell the T cell to become a T cell, and that's the function of notch. Notch is a very famous signal used in a number of developmental systems. Here, we have a signal coming from a cell up here, the signal is delta, it's a juxtacrine factor, and it's signalling to the T cell at the lower right, and eventually, it's telling it to become a T cell. This signaling pathway is a bit unusual because it doesn't involve phosphorylation, it involves a series of proteolytic enzymes that eventually cleave off the internal domain of notch and unleash it in the cytoplasm where it picks up another protein delta, heads into the nucleus, and begins to transcribe genes that will be characteristic of T cells. This particular pathway is named for its first discovery in fruit flies and when they found it in fruit flies, of course, fruit fly genes are named by what the fruit fly looks like when it doesn't work. So, in this case, the series of signals will produce funky looking wings in fruit flies, either notched, or delta-shaped, or serrated edges, or some other variation of a funky looking wing. This particular set of signals is really important in a number of mammalian development signals as well including those involved in T cell production. In particular, we're going to up-regulate some proteins that will allow our T cell to leave the bone marrow and head to the thymus, which is the next thing we're going to look at. That is, the T cell Progenitor will produce a membrane protein called CD44. CD44 is actually a designation for a family of proteins, and these are glycoproteins in the cell membrane that cause cells to essentially move around, leave one place, and wind up in another. CD44 was originally named homing cell adhesion molecule, and the particular CD44 that you make will cause the cell to home into a particular location. One of its forms actually is involved in metastatic cancer, that is getting things to pick up and move from where they should be and allow them to invade your body, that's a bad thing. But in this case, we have a good thing because this T cell Progenitor will have on, its surface, a membrane protein that will direct it to the thymus gland where all of the fun things are going to happen, which we'll start looking at in the next clip.
