# T cell priming

https://www.youtube.com/watch?v=GWv2GgI_DYA

[00:01] So in order to utilize our cell mediated immune response, the first thing we have to do is prime it.
[00:08] And just like a pump, you need to do things a little bit differently the first time around than the other times around.
[00:15] So when we're activating a naive T cell that has never before seen its antigen of interest for the very first time, it's going to have a different set of rules than it will once it's seen its antigen, is familiar with it, and knows how to find it.
[00:30] And this concept is called priming.
[00:32] It's similar to the term activating in that this is the first time our naive little T cell is going to grow up and see its antigen and get licensed to do what it's really supposed to do, to reach its full destiny.
[01:00] Now recall from our before, it hangs out in the T cell zone, which is the paracortex of the lymph.
[01:04] Node just like the lymph node antigens can come in through blood vessels or through the lymphatic duct and hang out in the lymph node as can te- cells and other things.
[01:15] Now if this little antigen is hanging out near a te- cell, it's not going to really do the te- cell any good or us any good for getting rid of the pathogen because the te- cell can't see it outside of the context of MHC.
[01:27] So lucky for us, there are dendritic cells CS that hang out within the lymph node and also dendritic cells that may have picked up the pathogen out in the periphery and have brought it to the lymph node to be able to re be recognized on MHC by the t- cell after they have processed it.
[01:49] But how do we make this happen?
[01:52] How do we first have t- cell and MHC meet?
[01:55] So let's go through the steps that are required to Prime the cell mediated immune response, and the first step is to create contact between.
[02:04] The T-cell and the antigen presenting cell.
[02:06] So once inside the lymph node, the T-cell needs to adhere to the dendritic cell before the TCR and the MHC can interact.
[02:13] So the first thing that's going to happen is that IAM 1 on the surface of the antigen presenting cell is going to meet up with LFA1 on the surface of the T-cell like this.
[02:24] Note that the length of IAM 1 is fairly long, whereas the length of the TCR is fairly short.
[02:30] So IAM 1 with LFA1 helps kind of bring it into the docking station, which allows the MHC molecule and the TCR molecules to interact at their invariant chains.
[02:44] This interaction is also aided by CD4 and CD8, which like IAM1 are fairly long and will bring the MHC molecule in close contact, kind of locking that interaction into place.
[02:57] I liken this LFA1-IAM1 interaction to shaking someone's hand.
[03:04] When you first meet them as opposed to giving them a giant big bear hug at this point, the association between IAM 1 and LFA 1 is fairly weak.
[03:15] It's just enough to bring the cells in close proximity so that the T cell can figure out if this is its antigen of interest.
[03:23] If the antigen within the MHC groove is the right antigen, the correct antigen for that TCR, that sends a signal to LFA 1 that it's got the right antigen and the interaction needs to get much stronger and quickly.
[03:37] So that will send a signal to LFA 1 to actually change its confirmation.
[03:42] This new confirmation of LFA 1 has a much stronger affinity for IAM 1, creating much stronger binding.
[03:50] As I mentioned, remember that the invariant sites of the MHC molecule will bind directly to the TCR molecule and CD4 or CD8 to the MHC molecule as well.
[04:02] This interaction here MHC TCR and CD4 or...
[04:07] CD8 is referred to as signal one of T-
[04:11] Cell Activation T- cells require two signals for Activation and a third signal to differentiate into their full potential.
[04:22] The second signal of T- Cell Activation is referred to as co- stimulation.
[04:28] Te- cells cannot be activated if there's there's no co- stimulation.
[04:32] It's kind of like a secondary control to say nope this is a real antigen this is the real show you found antigen respond.
[04:40] This co- stimulation is mediated by the B7 molecules on the antigen presenting s cell.
[04:45] The B7 molecules are known as b7.1 and b7.2.
[04:49] They can also be known as cd80 or cd86.
[04:53] You might see them in both in both terms um remember immunologists are mean like to name things twice but for the most part I'll refer to them as the B7 molecules.
[05:03] B7 will interact with a molecule known as
[05:08] CD28 on the surface of the T-cell when this ligation occurs in the presence of the correct antigen with MHC and TCR interacting, you have signal one and now signal two of T-cell activation.
[05:24] At this point, your T-cell is activated.
[05:27] Now what would happen if we had signal one over here with antigen and TCR and MHC but no signal two?
[05:37] Well, what happens then is that the cell becomes anergic, and I mentioned this earlier that occasionally when cells are not activated properly, they become kind of like zombie cells.
[05:51] Um, they are unable to react, and even if they see their antigen of interest again later in the presence of co-stimulation, they won't respond.
[06:00] The only way you can break anergy is by giving them a lot of IL2 because then they begin to get more signals that tell them, okay, maybe this is the real thing, but for the most part.
[06:09] They become completely unable to respond to that antigen in the future.
[06:14] Now the addition of signal to will lead to two key in key events.
[06:16] The first would be the induction of the high affinity IL-2 alpha receptor, which is known as CD25.
[06:27] Recall from our mechanisms of cytokine signaling video that all naive T-cells express the gamma and beta chain of the IL-2 receptor, but that only activated T-cells can express the IL-2 receptor alpha chain.
[06:41] When activated T-cells upregulate the IL-2 receptor alpha chain, and especially if they are a CD4 positive T helper cell, they'll begin producing their own IL-2.
[06:54] As they produce their IL-2, they can then take up that IL-2, and that results in the cell proliferating.
[07:00] This is really important because we need T-cell proliferation to create a nice vast army of T-cells capable of combating the effect in okay.
[07:10] So at this point we have created contact between the T and the B cell.
[07:14] We created signal one which was MHCT TCR interaction and signal 2 which is co-stimulation.
[07:25] Now we're going to add our last thing that we need to do and we need to differentiate the T-cell.
[07:29] This will be done using cytokines that are produced by the micro environment and the antigen presenting cell.
[07:37] At this point the antigen presenting cell will begin producing cytokines or cytokines from the micro environment.
[07:44] Say other cells that have been activated, other antigen presenting cells or T cells will produce cytokines that will influence the type of T-cell that will be differentiated.
[07:57] Even if it's a CD8 positive T-cell which doesn't have its own subsets other than the directive to kill target cells, these cytokines provide an important signal telling the CD8 positive T-cell it's time to go to.
[08:11] Work these cytokine kinds include IL-6, IL-12.
[08:16] TGF-beta and IL-4.
[08:18] Each of these cytokine kinds given in different concentrations or in different combinations can result in different effector functions for the T-cell.
[08:28] If it's a CD4 positive T-cell, and we'll cover how that works in another video looking at the different T-helper subsets that exist.
[08:40] The junction between the antigen presenting cell and the T-cell, and this space in between with all of the various receptor-ligand interactions, is referred to as the immune synapse.
[08:53] The immune synapse, just like your neuronal synapse that you just learned about in your neuro studies, is really just the border between the two cells where the cells are able to communicate.
[09:07] So in conclusion, when we're priming a naive T-cell for the first time, we have four steps you need to.
[09:12] First create contact between the T cell and the antigen presenting cell.
[09:14] And this is done through IAM and LFA1.
[09:16] Which then brings MHC and TCR in close proximity through the help of CD4 or CD8.
[09:23] MHC TCR binding is your signal one for activation.
[09:30] But that's not sufficient to activate a naive T cell.
[09:34] A naive T cell will also require co-stimulation.
[09:37] And that comes from CD28 on the T cell and B7 on the antigen presenting cell.
[09:42] Once this occurs, the CD4 positive T cell can begin making its own IL2.
[09:48] And both CD4 and CD8 positive T cells will upregulate expression of the high affinity IL2 receptor alpha chain known as CD25.
[09:57] This signal will allow it to proliferate.
[10:02] Lastly, IL2 plus a lot of other cytokines that I mentioned can promote the differentiation of the cell.
[10:06] For a CD8 positive T cell, it's going to license it to kill.
[10:11] For a CD4 positive T cell, it's going to license it to.
[10:13] Gain its true affector functions so that
[10:16] it can best help other cells clear
[10:18] pathogen.