WEBVTT 00:00:16.865 --> 00:00:17.740 PROFESSOR: All right. 00:00:17.740 --> 00:00:21.710 So today, we're going to talk about immunity again. 00:00:21.710 --> 00:00:27.100 And so this movie up on the screen here-- 00:00:27.100 --> 00:00:28.330 this is a cell. 00:00:28.330 --> 00:00:31.705 You can see the outline of the cells kind of around here. 00:00:31.705 --> 00:00:33.933 That's the outline of the cell. 00:00:33.933 --> 00:00:35.350 But what you can see is that there 00:00:35.350 --> 00:00:38.740 is something in the cell moving around, 00:00:38.740 --> 00:00:43.450 and that is an intracellular bacteria called listeria. 00:00:43.450 --> 00:00:47.020 And you can see it's rocketing around in this cell. 00:00:47.020 --> 00:00:50.110 It's having a total party in this cell, 00:00:50.110 --> 00:00:56.110 and what you'll see here is you can often see the bacteria push 00:00:56.110 --> 00:00:57.753 out from the cell. 00:00:57.753 --> 00:00:59.920 So if you look here, one is going to push right now. 00:00:59.920 --> 00:01:00.580 See? 00:01:00.580 --> 00:01:01.163 There it goes. 00:01:01.163 --> 00:01:03.520 And it kind of runs into the edge of the cell 00:01:03.520 --> 00:01:08.380 and pushes out, and this enables the bacteria 00:01:08.380 --> 00:01:11.950 to spread from cell to cell without actually going 00:01:11.950 --> 00:01:15.790 into the extracellular space surrounding the cells, OK? 00:01:18.660 --> 00:01:21.390 So let's take a hypothetical situation. 00:01:24.720 --> 00:01:27.360 So listeria is a foodborne illness. 00:01:27.360 --> 00:01:33.570 It causes a nasty sort of intestinal disease. 00:01:33.570 --> 00:01:38.490 So Brett, do you want these bacteria having 00:01:38.490 --> 00:01:39.600 a party in your cells? 00:01:39.600 --> 00:01:40.950 AUDIENCE: Unlikely. 00:01:40.950 --> 00:01:42.010 PROFESSOR: Hell no. 00:01:42.010 --> 00:01:46.710 OK, Malik, do you want these bacteria having 00:01:46.710 --> 00:01:48.840 a party in your cells? 00:01:48.840 --> 00:01:50.010 Hell no. 00:01:50.010 --> 00:01:52.890 Carmen, do you want these bacteria 00:01:52.890 --> 00:01:54.390 having a party in your cells? 00:01:54.390 --> 00:01:55.230 AUDIENCE: Hell no. 00:01:55.230 --> 00:01:56.140 PROFESSOR: Hell no! 00:01:56.140 --> 00:01:56.640 Yes. 00:01:56.640 --> 00:02:02.310 OK, so our body has to have some way to sort of address 00:02:02.310 --> 00:02:06.030 this type of an illness, and the problem 00:02:06.030 --> 00:02:11.440 is if you're thinking about what we discussed on Wednesday, is-- 00:02:11.440 --> 00:02:11.940 all right. 00:02:11.940 --> 00:02:14.220 So you're hosting this party, right? 00:02:14.220 --> 00:02:15.840 This is your cell. 00:02:15.840 --> 00:02:17.670 So you have a host cell-- 00:02:17.670 --> 00:02:24.000 that's your cell-- and you have an intracellular pathogen, 00:02:24.000 --> 00:02:27.360 such as a bacteria or it could also be a virus, 00:02:27.360 --> 00:02:30.660 and they're essentially using your generous host 00:02:30.660 --> 00:02:33.240 cell to reproduce itself to spread 00:02:33.240 --> 00:02:35.790 to other cells of the body. 00:02:35.790 --> 00:02:39.330 And so you don't want that, but the problem is that-- 00:02:39.330 --> 00:02:44.070 I told you about B cells, so remember B cells-- 00:02:44.070 --> 00:02:46.740 they have an antigen receptor. 00:02:46.740 --> 00:02:50.520 It's initially on their plasma membrane. 00:02:50.520 --> 00:02:55.740 It can also be secreted, and it's secreted 00:02:55.740 --> 00:02:58.030 into the extracellular space. 00:02:58.030 --> 00:03:02.410 The problem is that these pathogens are inside the cell, 00:03:02.410 --> 00:03:05.700 and there's a plasma membrane separating them 00:03:05.700 --> 00:03:10.950 from the antigen receptors that you need to recognize them, OK? 00:03:10.950 --> 00:03:14.050 So this presents an issue. 00:03:14.050 --> 00:03:18.270 It's also the case for T cells, because as you heard 00:03:18.270 --> 00:03:22.440 on Wednesday, T cells only have this membrane-bound form 00:03:22.440 --> 00:03:27.900 of the receptor, and the antigen recognition domains of all 00:03:27.900 --> 00:03:32.640 of these are extracellular, so there is really-- 00:03:32.640 --> 00:03:36.390 with just this system, there's no way for your immune cells 00:03:36.390 --> 00:03:38.490 to see in the cells. 00:03:38.490 --> 00:03:40.650 So today, I want to talk about how 00:03:40.650 --> 00:03:44.040 is it that the immune cells are able-- 00:03:44.040 --> 00:03:47.460 how our immune cells are able to see within the cell 00:03:47.460 --> 00:03:53.340 in order to address an infection like this one, with listeria. 00:03:53.340 --> 00:03:54.480 OK? 00:03:54.480 --> 00:03:57.180 And the first part of the answer is 00:03:57.180 --> 00:04:01.610 that it involves a process known as antigen presentation. 00:04:09.870 --> 00:04:13.640 And antigen presentation is the process 00:04:13.640 --> 00:04:21.140 by which peptides, so short sequences of amino acids, 00:04:21.140 --> 00:04:25.250 are presented and displayed on the surface of the cell 00:04:25.250 --> 00:04:26.990 for the immune system-- 00:04:26.990 --> 00:04:28.580 for immune cells to see. 00:04:28.580 --> 00:04:50.080 So here, peptides are displayed on the cell surface 00:04:50.080 --> 00:04:51.730 for immune cells to see them. 00:04:51.730 --> 00:04:55.810 And in this specific case, it's going to be for the T cells 00:04:55.810 --> 00:05:00.060 to observe what's going on inside the cell, OK? 00:05:03.040 --> 00:05:07.360 So this mechanism involves another molecule, 00:05:07.360 --> 00:05:09.840 which I briefly introduced. 00:05:09.840 --> 00:05:21.280 It's called the major histocompatibility complex, 00:05:21.280 --> 00:05:24.070 which is abbreviated MHC. 00:05:24.070 --> 00:05:28.420 So when I referred to MHC in Wednesday's lecture, 00:05:28.420 --> 00:05:31.810 I was referring to this major histocompatibility complex. 00:05:34.550 --> 00:05:38.920 And there are two classes of MHCs. 00:05:38.920 --> 00:05:43.620 Thankfully, the first one is known as class 1, 00:05:43.620 --> 00:05:52.600 so class 1 MHC, and class 1 MHC looks like this. 00:05:52.600 --> 00:05:55.810 Like many of the immune receptors 00:05:55.810 --> 00:06:00.250 that I've talked about, it has a heavy chain, 00:06:00.250 --> 00:06:04.150 which is this long polypeptide light blue, 00:06:04.150 --> 00:06:07.630 and it has a light chain in purple. 00:06:07.630 --> 00:06:12.430 So the MHC is composed of these two separate polypeptides. 00:06:12.430 --> 00:06:14.830 They're encoded by different genes, 00:06:14.830 --> 00:06:19.100 and then it assembles into this structure shown here. 00:06:19.100 --> 00:06:22.720 So this molecule has two Ig domains, 00:06:22.720 --> 00:06:26.450 and these are proximal to the plasma membrane. 00:06:26.450 --> 00:06:28.850 And this thing is all inserted in the plasma membrane. 00:06:28.850 --> 00:06:31.780 It's an integral membrane protein. 00:06:31.780 --> 00:06:34.780 And then distal to the plasma membrane 00:06:34.780 --> 00:06:37.390 is this structure here, and if you 00:06:37.390 --> 00:06:40.330 look at the crystal structure, it's kind of like a sheet-- 00:06:40.330 --> 00:06:44.710 a beta sheet with two alpha helices. 00:06:44.710 --> 00:06:48.130 And altogether what it does is it basically creates, 00:06:48.130 --> 00:06:50.890 like, a little cup, OK? 00:06:50.890 --> 00:06:53.590 So it's creating, like, a cup. 00:06:53.590 --> 00:06:58.690 And what sits in this cup is a peptide, so you get peptides, 00:06:58.690 --> 00:07:02.560 and the peptides sort of sit in that hand, if you will. 00:07:02.560 --> 00:07:06.540 And some of the amino acids from that peptide are sticking out 00:07:06.540 --> 00:07:10.750 and they're sort of displayed away from the MHC molecule. 00:07:13.780 --> 00:07:18.700 So this is basically a hand that holds peptides and displays 00:07:18.700 --> 00:07:23.440 them on the outside of the cell, right? 00:07:23.440 --> 00:07:25.990 So the outside of the cell here is up. 00:07:25.990 --> 00:07:28.300 This would be the exoplasm out here, 00:07:28.300 --> 00:07:31.090 and it's displaying these peptides for immune cells 00:07:31.090 --> 00:07:32.575 like T cells to observe. 00:07:36.840 --> 00:07:37.340 All right. 00:07:37.340 --> 00:07:41.660 So class 1 MHC is a class that's expressed 00:07:41.660 --> 00:07:48.350 on all nucleated cells in your body. 00:07:51.530 --> 00:07:54.320 So that's all of your nucleotide cells 00:07:54.320 --> 00:07:58.370 are synthesizing in a class 1 MHC, 00:07:58.370 --> 00:08:02.660 and then it's sort of being displayed on the surface. 00:08:02.660 --> 00:08:06.470 And the peptides that are held by this class 1 MHC-- 00:08:09.630 --> 00:08:12.620 the peptides here are being derived 00:08:12.620 --> 00:08:17.720 from a specific place in the cell, which is the cytoplasm. 00:08:17.720 --> 00:08:21.990 So the peptides are from the cytoplasm, 00:08:21.990 --> 00:08:27.170 so this is the source of the peptides, 00:08:27.170 --> 00:08:31.610 and I'll tell you how these peptides are sort of loaded 00:08:31.610 --> 00:08:34.890 on to this MHC molecule. 00:08:34.890 --> 00:08:39.919 So the MHC molecule is a membrane protein, 00:08:39.919 --> 00:08:45.050 so it's translated on the endoplasmic reticulum, 00:08:45.050 --> 00:08:47.780 and its extracellular domain is initially 00:08:47.780 --> 00:08:51.170 present in the lumen of the ER. 00:08:51.170 --> 00:08:53.150 And the peptides are from proteins 00:08:53.150 --> 00:08:55.520 that are present in the cytoplasm, 00:08:55.520 --> 00:08:57.920 and what happens to these proteins-- 00:08:57.920 --> 00:09:01.890 and this occurs for unfolded proteins, 00:09:01.890 --> 00:09:05.150 but also for proteins that might be ubiquitinated-- 00:09:05.150 --> 00:09:08.420 is that they're processed by the proteasome, which 00:09:08.420 --> 00:09:14.990 is this kind of a shredder-like function for proteins, 00:09:14.990 --> 00:09:20.300 and it cuts up the proteins into little snippets, or peptides, 00:09:20.300 --> 00:09:23.960 that can then be pumped into the lumen of the ER 00:09:23.960 --> 00:09:26.000 through this transporter, TAP. 00:09:26.000 --> 00:09:28.970 So these peptides can be taken and transported 00:09:28.970 --> 00:09:31.340 into the lumen of the ER, and that's 00:09:31.340 --> 00:09:35.570 where they're loaded onto the class 1 MHC molecule. 00:09:35.570 --> 00:09:38.570 But the source peptides is from proteins 00:09:38.570 --> 00:09:40.100 that are in the cytoplasm. 00:09:40.100 --> 00:09:43.520 They're processed by the proteasome. 00:09:43.520 --> 00:09:47.390 So then, once you have a peptide-MHC complex, 00:09:47.390 --> 00:09:50.090 it can then be trafficked through the normal vesicle 00:09:50.090 --> 00:09:53.780 trafficking pathway all the way out to the plasma membrane 00:09:53.780 --> 00:09:57.440 of the cell where now that peptide will be displayed 00:09:57.440 --> 00:10:00.040 for T cells to observe. 00:10:03.110 --> 00:10:05.180 And so the peptides here, they're 00:10:05.180 --> 00:10:09.470 processed by the proteasome-- 00:10:09.470 --> 00:10:13.670 processed or cut by the proteasome-- 00:10:19.010 --> 00:10:21.440 and then the type of T cell that's 00:10:21.440 --> 00:10:25.190 going to look at these class 1 molecules-- 00:10:25.190 --> 00:10:28.970 they are known as seeds CD8 positive T cells. 00:10:33.080 --> 00:10:37.350 So this is the first class of MHC molecule. 00:10:37.350 --> 00:10:39.170 Because there is a class 1, that means 00:10:39.170 --> 00:10:42.740 there also must be a class 2, which there is. 00:10:42.740 --> 00:10:49.730 And so class 2 MHCs are fundamentally different in all 00:10:49.730 --> 00:10:50.840 of these properties. 00:10:53.990 --> 00:10:58.310 The function shared by these MHC molecules 00:10:58.310 --> 00:11:02.670 is they both display peptides on the surface of the cell. 00:11:02.670 --> 00:11:08.660 So MHC molecules do display peptides 00:11:08.660 --> 00:11:13.190 on the surface, which is known as antigen presentation. 00:11:13.190 --> 00:11:18.320 But other than that, MHC class 2 is pretty different. 00:11:18.320 --> 00:11:21.170 You see the structure of MHC class 2 00:11:21.170 --> 00:11:24.920 is very similar to that of class 1, 00:11:24.920 --> 00:11:27.080 but you see that rather than having 00:11:27.080 --> 00:11:29.030 a heavy and a light chain, here there 00:11:29.030 --> 00:11:33.320 are two chains that are roughly of equal size. 00:11:33.320 --> 00:11:36.550 And so these are encoded by different genes 00:11:36.550 --> 00:11:42.350 than the class 1 molecule, and they encode different proteins. 00:11:42.350 --> 00:11:47.760 But the overall structural similarity is very similar, 00:11:47.760 --> 00:11:49.640 so there are two Ig domains, they're 00:11:49.640 --> 00:11:52.910 proximal to the plasma membrane, and then there's 00:11:52.910 --> 00:11:58.250 this structure at the very end of the MHC molecule, 00:11:58.250 --> 00:12:00.560 which has this groove in it which 00:12:00.560 --> 00:12:03.110 can hold a peptide that would be displayed 00:12:03.110 --> 00:12:06.390 on the surface of the cell. 00:12:06.390 --> 00:12:09.410 And there, you see the groove and you see the peptide 00:12:09.410 --> 00:12:12.610 that is present in it. 00:12:12.610 --> 00:12:18.170 All right, so one big difference between class 1 and class 2 00:12:18.170 --> 00:12:22.640 is that class 2 is expressed on a much more restricted set 00:12:22.640 --> 00:12:23.990 of cells. 00:12:23.990 --> 00:12:29.030 So class 2 MHCs are expressed specifically on specialized 00:12:29.030 --> 00:12:38.120 cells known as antigen-presenting cells, 00:12:38.120 --> 00:12:43.040 and these antigen presenting cells include cells like B 00:12:43.040 --> 00:12:48.230 cells, which are the ones that I'll focus on, but also 00:12:48.230 --> 00:12:53.300 phagocytic that can phagocytose foreign substances-- 00:12:58.390 --> 00:13:04.280 phagocytic cells-- and there's another cell type 00:13:04.280 --> 00:13:06.500 called the dendritic cell, which is also 00:13:06.500 --> 00:13:08.270 an antigen-presenting cell. 00:13:08.270 --> 00:13:10.880 I'm going to focus on the B cells. 00:13:10.880 --> 00:13:13.730 So class 1 is expressed everywhere. 00:13:13.730 --> 00:13:16.760 Class 2 is really expressed on these professional 00:13:16.760 --> 00:13:18.290 antigen-presenting cells. 00:13:20.958 --> 00:13:23.660 And the way that the peptides-- 00:13:23.660 --> 00:13:26.960 the source of the peptides and the way they're generated 00:13:26.960 --> 00:13:29.270 is also very different. 00:13:29.270 --> 00:13:37.700 So peptides for class 2 come from the extracellular space, 00:13:37.700 --> 00:13:42.020 and they are processed by lysosomal proteases. 00:13:53.190 --> 00:13:56.720 And so I'll show you how that looks in cartoon form. 00:13:59.550 --> 00:14:02.810 So for MHC class 2, the peptides are 00:14:02.810 --> 00:14:05.420 from the extracellular space. 00:14:05.420 --> 00:14:09.590 And so we've talked about ways that cells 00:14:09.590 --> 00:14:11.030 can take in material. 00:14:11.030 --> 00:14:13.400 One way is through endocytosis, right? 00:14:13.400 --> 00:14:15.950 So if this is my antigen, the antigen 00:14:15.950 --> 00:14:20.600 could be endocytosed by the cell, 00:14:20.600 --> 00:14:26.300 and now it's in a vesicle that's present in the cell. 00:14:26.300 --> 00:14:29.360 And so if you endocytose this protein, 00:14:29.360 --> 00:14:33.500 then it's now in a vesicle, and one compartment 00:14:33.500 --> 00:14:35.660 that it can go to is the lysosome, 00:14:35.660 --> 00:14:38.840 where are these there are these lysosomal proteases they 00:14:38.840 --> 00:14:41.840 can then chop up this protein into little snippets, 00:14:41.840 --> 00:14:44.370 or peptides. 00:14:44.370 --> 00:14:48.140 And so MHC class 2, again, is translated 00:14:48.140 --> 00:14:49.820 at the end of endoplasmic reticulum, 00:14:49.820 --> 00:14:51.815 like all plasma membrane proteins. 00:14:55.430 --> 00:14:57.470 But in the endoplasmic reticulum, 00:14:57.470 --> 00:15:00.740 you see the peptide groove is blocked such 00:15:00.740 --> 00:15:03.770 that peptides derived from the cytoplasm 00:15:03.770 --> 00:15:07.490 can't interact with class 2, but then 00:15:07.490 --> 00:15:11.870 is trafficked to a unique compartment which can combine 00:15:11.870 --> 00:15:16.100 with the compartment that has the peptides that originated 00:15:16.100 --> 00:15:17.990 from outside the cell. 00:15:17.990 --> 00:15:22.700 And then those can get loaded onto this class 2 MHC molecule, 00:15:22.700 --> 00:15:25.970 and then this can be recognized by T cells. 00:15:25.970 --> 00:15:28.884 But in this case, it is a-- 00:15:28.884 --> 00:15:30.980 oh, I endocytosed my chalk. 00:15:30.980 --> 00:15:32.230 I need to get it back. 00:15:32.230 --> 00:15:33.110 Here. 00:15:33.110 --> 00:15:38.630 So in this case, it's not a CD8 T cell that's recognizing it, 00:15:38.630 --> 00:15:40.670 but a CD4 positive T cell. 00:15:45.150 --> 00:15:49.640 OK, so let me briefly review what I just went through, 00:15:49.640 --> 00:15:53.840 and review the differences between class 1 and class 2. 00:15:53.840 --> 00:15:58.010 So class 1 MHC is expressed on all nucleated cells, 00:15:58.010 --> 00:16:00.290 whereas class 2 is much more restricted, 00:16:00.290 --> 00:16:04.385 being expressed specifically on antigen-presenting cells. 00:16:07.100 --> 00:16:10.940 The T cells that recognize these two classes are different. 00:16:10.940 --> 00:16:14.570 Class 1's recognized by CD8 positive T cells. 00:16:14.570 --> 00:16:20.060 Class 2 is recognized by CD4 positive T cells. 00:16:20.060 --> 00:16:24.570 And the source of the antigen is different in these two cases. 00:16:24.570 --> 00:16:27.980 The source of the antigen for class 1 is the cytoplasm. 00:16:27.980 --> 00:16:32.090 For class 2, it's the extracellular space. 00:16:32.090 --> 00:16:35.030 So the different MHCs are sampling different sort 00:16:35.030 --> 00:16:38.330 of pools of proteins. 00:16:38.330 --> 00:16:40.820 And where the peptide is loaded is 00:16:40.820 --> 00:16:42.680 distinct between these two, which 00:16:42.680 --> 00:16:45.680 allows these distinct classes to basically 00:16:45.680 --> 00:16:48.500 discriminate between the sources of the peptides 00:16:48.500 --> 00:16:50.090 that they're loading. 00:16:50.090 --> 00:16:52.280 So for class 1, that's in the ER. 00:16:52.280 --> 00:16:56.600 For class 2, it arises from a vesicle compartment 00:16:56.600 --> 00:17:00.380 that results from endocytosis of an antigen 00:17:00.380 --> 00:17:01.670 from outside the cell. 00:17:06.869 --> 00:17:07.440 All right. 00:17:07.440 --> 00:17:11.640 Now, the type of molecule that recognizes this MHC 00:17:11.640 --> 00:17:18.950 peptide complex is the T cell receptor, which I briefly 00:17:18.950 --> 00:17:21.290 outlined on Wednesday, but now we're 00:17:21.290 --> 00:17:24.290 going to talk about it in much more detail. 00:17:24.290 --> 00:17:30.180 So the T cell receptor, or TCR-- 00:17:30.180 --> 00:17:34.250 and I talked about its structure which is shown up on the slide, 00:17:34.250 --> 00:17:36.620 but I'll just draw more simply here. 00:17:36.620 --> 00:17:41.070 If this is the plasma membrane, this is the cytoplasm, 00:17:41.070 --> 00:17:44.900 and this is the exoplasm facing down, 00:17:44.900 --> 00:17:48.200 then this T cell receptor has two chains. 00:17:48.200 --> 00:17:52.370 One is called the alpha chain, and the second 00:17:52.370 --> 00:17:53.495 is called the beta chain. 00:17:56.390 --> 00:18:00.590 And each is comprised of two Ig domains, 00:18:00.590 --> 00:18:02.930 which you see up there. 00:18:02.930 --> 00:18:06.830 So the T cell receptor here is in pink. 00:18:06.830 --> 00:18:09.740 You can see an Ig domain there on one strand-- 00:18:09.740 --> 00:18:11.990 Ig domain there. 00:18:11.990 --> 00:18:18.650 And you have another two Ig domains on the other subunit, 00:18:18.650 --> 00:18:21.800 and this receptor, the T cell receptor, 00:18:21.800 --> 00:18:27.470 recognizes antigens through its variable domain, which is here. 00:18:27.470 --> 00:18:31.580 And it's binding basically to the end of this receptor, 00:18:31.580 --> 00:18:35.990 so this is a sort of ribbon diagram of a structure for a T 00:18:35.990 --> 00:18:37.040 cell receptor. 00:18:37.040 --> 00:18:39.270 The plasma membrane would be up here. 00:18:39.270 --> 00:18:41.930 This is the end of the T cell receptor. 00:18:41.930 --> 00:18:45.740 And MHC is in green, and it's holding a peptide here 00:18:45.740 --> 00:18:47.100 in yellow. 00:18:47.100 --> 00:18:52.190 And you can see how the TCR is sort of interacting or docking 00:18:52.190 --> 00:18:54.290 to this MHC-peptide complex. 00:18:57.380 --> 00:19:04.920 So for the T cell receptor to interact and bind to MHC, 00:19:04.920 --> 00:19:07.070 you have to have a T cell receptor that 00:19:07.070 --> 00:19:09.290 recognizes the specific conformation 00:19:09.290 --> 00:19:12.830 of the peptide that is being sort of extended away 00:19:12.830 --> 00:19:14.480 from the cell. 00:19:14.480 --> 00:19:17.510 So let's say this is my T cell receptor, 00:19:17.510 --> 00:19:20.210 and I'm going around and searching for cells that 00:19:20.210 --> 00:19:22.100 might want to look at this. 00:19:22.100 --> 00:19:25.880 Then if I had a T cell receptor that was like this, 00:19:25.880 --> 00:19:28.100 it's not going to be able to stick 00:19:28.100 --> 00:19:32.610 to this MHC-peptide complex. 00:19:32.610 --> 00:19:35.420 However, if I had a T cell receptor that 00:19:35.420 --> 00:19:37.270 had the right conformation, because there 00:19:37.270 --> 00:19:39.560 are different types of T cell receptors, 00:19:39.560 --> 00:19:42.650 it might be able to dock on and stick to the peptide, 00:19:42.650 --> 00:19:49.880 and then the T cell is now stuck to the peptide-MHC complex, OK? 00:19:49.880 --> 00:19:52.040 So there are different T cell receptors. 00:19:52.040 --> 00:19:54.470 There's a diversity of T cell receptors, 00:19:54.470 --> 00:19:58.280 and they're able to discriminate between different peptides 00:19:58.280 --> 00:19:59.255 loaded onto MHC. 00:20:07.530 --> 00:20:10.680 OK, so now, we have to think about where this diversity of T 00:20:10.680 --> 00:20:12.180 cell receptors comes from. 00:20:15.600 --> 00:20:20.130 There's a diversity of TCRs, and lucky for you, 00:20:20.130 --> 00:20:23.610 the mechanism that generates the diversity of TCRs 00:20:23.610 --> 00:20:28.470 is the same that generates diversity for antibodies. 00:20:28.470 --> 00:20:31.320 Now, Georgia asked a really good and really important 00:20:31.320 --> 00:20:34.750 question at the end of lecture on Wednesday, 00:20:34.750 --> 00:20:38.820 which is-- she asked if this sort of rearrangement 00:20:38.820 --> 00:20:44.430 of gene segments in the variable domain of the antibody 00:20:44.430 --> 00:20:49.340 was due to splicing or recombination 00:20:49.340 --> 00:20:51.480 at the genomic locus. 00:20:51.480 --> 00:20:53.610 And the answer is that it's recombination 00:20:53.610 --> 00:20:58.270 at the genomic locus, and that's a very important point. 00:20:58.270 --> 00:21:01.920 So here's a diagram for the beta chain of the TCR. 00:21:01.920 --> 00:21:05.290 You can see that like the B cell receptor, 00:21:05.290 --> 00:21:08.820 there's a gene rearrangement in the genomic DNA that 00:21:08.820 --> 00:21:11.490 brings V, D, and J segments together to make 00:21:11.490 --> 00:21:15.510 the variable chain of the T cell receptor. 00:21:15.510 --> 00:21:24.930 So like the B cell receptor, there is a gene rearrangement, 00:21:24.930 --> 00:21:33.330 also known as VDJ recombination, and this is not 00:21:33.330 --> 00:21:35.310 splicing of the transcript. 00:21:35.310 --> 00:21:37.110 This is in the genomic DNA-- 00:21:37.110 --> 00:21:40.890 a very important point, because by having 00:21:40.890 --> 00:21:44.250 this happen in the genomic DNA, it 00:21:44.250 --> 00:21:48.810 creates an irreversible change in that genomic DNA 00:21:48.810 --> 00:21:51.330 such that all subsequent cells that 00:21:51.330 --> 00:21:55.050 are derived from that original B or T cell 00:21:55.050 --> 00:22:00.480 are going to express the identical B or T cell receptor. 00:22:00.480 --> 00:22:02.850 So it's not splicing, but it's a real sort 00:22:02.850 --> 00:22:06.150 of irreversible change to the genomic DNA. 00:22:10.290 --> 00:22:14.070 So you have a diversity of T cell receptors, but the T cell 00:22:14.070 --> 00:22:17.100 receptor is not the only thing that 00:22:17.100 --> 00:22:22.500 enables the T cell to interact with whatever cell 00:22:22.500 --> 00:22:27.060 is presenting the antigen. There are these other co-receptors 00:22:27.060 --> 00:22:30.070 which are important. 00:22:30.070 --> 00:22:34.680 So there are co-receptors on the T cell-- 00:22:34.680 --> 00:22:36.000 this is on the T cell-- 00:22:38.730 --> 00:22:44.250 and the co-receptors are CD4 and CD8, 00:22:44.250 --> 00:22:46.845 and they're expressed on different subsets of T cells. 00:22:51.540 --> 00:22:54.960 And these co-receptors-- because it's not sufficient 00:22:54.960 --> 00:22:59.370 for just the T cell receptor to interact 00:22:59.370 --> 00:23:02.490 with a specific peptide, it also requires 00:23:02.490 --> 00:23:06.630 this co-receptor in order to get an immune response. 00:23:06.630 --> 00:23:08.640 So the logic is that if the T cell 00:23:08.640 --> 00:23:15.660 receptor and the co-receptor both bind to the MHC, 00:23:15.660 --> 00:23:20.340 then you get a particular type of response, so you need both. 00:23:20.340 --> 00:23:27.810 And CD4 cells recognize the class 2 of MHC. 00:23:32.330 --> 00:23:37.475 CD8 recognizes class 1 MHC. 00:23:46.950 --> 00:23:50.880 So you have these two different subsets of T cells 00:23:50.880 --> 00:23:56.850 and they recognize these distinct MHC complexes. 00:23:56.850 --> 00:24:00.600 So my question for you is what should these CD8 positive T 00:24:00.600 --> 00:24:01.410 cells do? 00:24:04.295 --> 00:24:05.670 To help with that, you might want 00:24:05.670 --> 00:24:09.840 to look at where the peptides are coming from that 00:24:09.840 --> 00:24:14.610 are presented on the class 1 MHCs, which are going to be 00:24:14.610 --> 00:24:18.600 presenting specifically to CD8. 00:24:18.600 --> 00:24:19.650 So what should these do? 00:24:24.630 --> 00:24:31.670 What does it mean if you have a class 1 MHC molecule containing 00:24:31.670 --> 00:24:32.890 a peptide that looks foreign? 00:24:35.930 --> 00:24:39.470 Well, where do the peptides come from? 00:24:39.470 --> 00:24:42.000 What's that, Patricia? 00:24:42.000 --> 00:24:42.940 Patricia is right. 00:24:42.940 --> 00:24:44.700 They're coming from the cytosol. 00:24:44.700 --> 00:24:48.120 So if you have foreign elements coming from the cytosol, 00:24:48.120 --> 00:24:49.940 what might that mean for that cell? 00:24:52.560 --> 00:24:57.250 Good, bad, irrelevant? 00:24:57.250 --> 00:24:58.090 What's that? 00:24:58.090 --> 00:25:00.340 AUDIENCE: [INAUDIBLE] 00:25:01.112 --> 00:25:02.070 PROFESSOR: What's that? 00:25:02.070 --> 00:25:04.210 OK, Brett's saying it needs to be dealt with, 00:25:04.210 --> 00:25:05.690 and I totally agree. 00:25:05.690 --> 00:25:07.920 Here's one scenario-- would be the scenario 00:25:07.920 --> 00:25:09.960 I showed you in the beginning of class 00:25:09.960 --> 00:25:13.110 where you have some sort of intracellular parasite 00:25:13.110 --> 00:25:17.460 that is basically using the host cell for its own evil purposes 00:25:17.460 --> 00:25:22.350 to produce more viruses or more bacteria. 00:25:22.350 --> 00:25:27.780 So if the immune cell has some sort of indication 00:25:27.780 --> 00:25:31.760 that this is going wrong, another example is in cancer, 00:25:31.760 --> 00:25:36.450 because if you have oncogenic mutations in certain genes, 00:25:36.450 --> 00:25:39.520 then those could be recognized as foreign. 00:25:39.520 --> 00:25:42.540 And so an appropriate response might 00:25:42.540 --> 00:25:45.300 be to do something to that cell that would limit 00:25:45.300 --> 00:25:47.820 the expansion of the tumor. 00:25:47.820 --> 00:25:50.880 Or in the case of an intracellular parasite, 00:25:50.880 --> 00:25:54.030 you really need to terminate the cell 00:25:54.030 --> 00:25:57.360 so that you stem the tide of viruses that are going 00:25:57.360 --> 00:26:00.210 to be produced by that cell. 00:26:00.210 --> 00:26:03.410 So the response should be to kill. 00:26:03.410 --> 00:26:04.950 So it was CD8 positive. 00:26:10.260 --> 00:26:13.755 If you have a CD8 positive T cell, 00:26:13.755 --> 00:26:17.400 it indicates there's something wrong inside that cell, 00:26:17.400 --> 00:26:21.750 and the response should be to kill it. 00:26:21.750 --> 00:26:25.020 And these CD8 positive T cells are known 00:26:25.020 --> 00:26:33.175 as killer or cytotoxic T cells. 00:26:37.610 --> 00:26:42.080 So what happens if a CD8 positive T cell recognizes 00:26:42.080 --> 00:26:47.270 a MHC class 1 peptide complex, then it 00:26:47.270 --> 00:26:52.070 releases materials from inside it that perforate that cell 00:26:52.070 --> 00:26:55.040 and lead it to undergo cell death. 00:26:55.040 --> 00:26:57.050 So it's a way of limiting an infection 00:26:57.050 --> 00:27:01.430 by killing the cells that the virus or pathogen is 00:27:01.430 --> 00:27:04.540 using to reproduce itself. 00:27:04.540 --> 00:27:09.230 OK, what about CD4 positive? 00:27:09.230 --> 00:27:12.390 What should be the response of a CD4 positive T cell? 00:27:18.220 --> 00:27:19.630 Should it also kill? 00:27:19.630 --> 00:27:24.240 Should be like the T-1000? 00:27:24.240 --> 00:27:26.160 No one gets my cultural references. 00:27:26.160 --> 00:27:27.880 Yeah. 00:27:27.880 --> 00:27:30.100 Should it be the Terminator 2? 00:27:30.100 --> 00:27:31.330 No. 00:27:31.330 --> 00:27:31.830 Yes or no? 00:27:31.830 --> 00:27:33.180 Who thinks it should terminate? 00:27:36.560 --> 00:27:37.850 OK. 00:27:37.850 --> 00:27:39.885 Steven, can you tell us your logic? 00:27:42.490 --> 00:27:43.690 Why should it not terminate? 00:27:43.690 --> 00:27:46.400 AUDIENCE: Because it's a [INAUDIBLE] B 00:27:46.400 --> 00:27:50.460 cell from the same [INAUDIBLE]. 00:27:50.460 --> 00:27:54.030 PROFESSOR: What are the MHC class 2 cells? 00:27:54.030 --> 00:27:56.693 AUDIENCE: Like, a B cell or [INAUDIBLE].. 00:27:56.693 --> 00:27:57.360 PROFESSOR: Yeah. 00:27:57.360 --> 00:27:58.902 It's not only a B cell, it's a B cell 00:27:58.902 --> 00:28:01.477 that recognizes the foreign agent 00:28:01.477 --> 00:28:02.560 that you're infected with. 00:28:02.560 --> 00:28:04.185 Yeah, Brett? 00:28:04.185 --> 00:28:08.280 AUDIENCE: So those B cells are antigen presenting cells. 00:28:08.280 --> 00:28:10.528 They have the information about what is bad 00:28:10.528 --> 00:28:13.200 or what is wrong in probably other cells? 00:28:13.200 --> 00:28:15.250 So like, oh, hey, we have this information. 00:28:15.250 --> 00:28:17.700 You should go and mobilize. 00:28:17.700 --> 00:28:19.200 PROFESSOR: They're binding something 00:28:19.200 --> 00:28:22.560 that it recognizes as foreign, internalizing it, and then 00:28:22.560 --> 00:28:25.500 presenting bits of that foreign element 00:28:25.500 --> 00:28:26.610 on the outside of itself. 00:28:26.610 --> 00:28:27.440 AUDIENCE: Shoots the messenger. 00:28:27.440 --> 00:28:27.870 PROFESSOR: What's that? 00:28:27.870 --> 00:28:29.610 It's shooting the messenger, exactly. 00:28:29.610 --> 00:28:30.630 Yeah. 00:28:30.630 --> 00:28:36.580 So it would be an extremely bad idea for the CD4 positive T 00:28:36.580 --> 00:28:39.930 cell to kill what's presenting the antigen, 00:28:39.930 --> 00:28:44.100 because you would kill the exact cell that you would need 00:28:44.100 --> 00:28:45.960 to fight that antigen, right? 00:28:45.960 --> 00:28:47.500 Here you have a B cell. 00:28:47.500 --> 00:28:50.730 It would be a B cell that's producing an antibody that 00:28:50.730 --> 00:28:52.980 actually can produce antibodies that 00:28:52.980 --> 00:28:56.790 might be able to neutralize that foreign invader, 00:28:56.790 --> 00:28:58.950 and so you don't want to kill it. 00:28:58.950 --> 00:29:03.880 You want to help it or enhance the B cell function. 00:29:08.660 --> 00:29:19.260 And so these CD4 positive cells are known as helper T cells, 00:29:19.260 --> 00:29:24.000 and they enhance B cell function in a number of different ways. 00:29:24.000 --> 00:29:27.000 Oh, I should point out where this happens. 00:29:27.000 --> 00:29:30.630 So this sort of interaction between B and T cells 00:29:30.630 --> 00:29:34.740 happens in the lymph node, because in the lymph node, 00:29:34.740 --> 00:29:38.280 you have antigen-presenting cells, or even 00:29:38.280 --> 00:29:41.970 soluble antigens, coming into these lymph nodes. 00:29:41.970 --> 00:29:44.400 And you also have B and T cells, and this 00:29:44.400 --> 00:29:47.670 is kind of like the B and T cell hangout 00:29:47.670 --> 00:29:50.820 to get sort of, like, interactions between these two 00:29:50.820 --> 00:29:52.920 distinct immune cell types. 00:29:55.470 --> 00:29:58.920 And when you get sort of a B cell 00:29:58.920 --> 00:30:02.580 that presents an antigen that's recognized by a T cell, 00:30:02.580 --> 00:30:05.760 then the T cell enhances B cell function, 00:30:05.760 --> 00:30:09.040 and it does so in a number of different ways. 00:30:09.040 --> 00:30:13.440 The first way that it induces a response in the B cell, 00:30:13.440 --> 00:30:15.480 known as affinity maturation. 00:30:21.740 --> 00:30:26.340 And this affinity maturation results from a hypermutation 00:30:26.340 --> 00:30:29.250 of the variable domain of the antibody such 00:30:29.250 --> 00:30:31.950 that you get even more diversity, and such 00:30:31.950 --> 00:30:36.390 that a B cell can be selected that even has a tighter binding 00:30:36.390 --> 00:30:38.670 to the antigen. 00:30:38.670 --> 00:30:41.550 So for affinity maturation, this is 00:30:41.550 --> 00:30:46.500 responsible for the transition in binding 00:30:46.500 --> 00:30:50.980 from a more weak binding to a tighter binding, 00:30:50.980 --> 00:30:52.950 which I talked about as being a difference 00:30:52.950 --> 00:30:56.610 between the primary infection and the secondary sort 00:30:56.610 --> 00:30:58.710 of immune response, OK? 00:30:58.710 --> 00:31:02.250 So the antibodies get better because of this B and T cell 00:31:02.250 --> 00:31:05.130 interaction and this affinity maturation process. 00:31:08.230 --> 00:31:13.410 One other thing that happens is that the B cells can produce 00:31:13.410 --> 00:31:17.580 different classes or isotypes of antibodies, 00:31:17.580 --> 00:31:20.162 and this is known as isotype switching. 00:31:29.330 --> 00:31:32.150 And so this is, again, the genomic locus 00:31:32.150 --> 00:31:37.430 for the heavy chain of an immunoglobulin. 00:31:37.430 --> 00:31:39.740 You see, here's the VDJ segment, so it's 00:31:39.740 --> 00:31:43.400 undergone VDJ recombination, and then 00:31:43.400 --> 00:31:47.000 what you see are these different blue regions here. 00:31:47.000 --> 00:31:51.380 Each of these are exons that encode a different isotope 00:31:51.380 --> 00:31:53.840 for the antibody. 00:31:53.840 --> 00:31:56.000 So the first one is mu, and so that 00:31:56.000 --> 00:32:02.300 produces IgM when that's the one that's proximal to VDJ. 00:32:02.300 --> 00:32:08.560 So if you have IgM, that's the initial state of the antibody, 00:32:08.560 --> 00:32:10.820 and that's initially membrane bound 00:32:10.820 --> 00:32:14.350 and serves as the B cell receptor. 00:32:14.350 --> 00:32:18.320 But each of these different constant domains, 00:32:18.320 --> 00:32:20.870 even though they're not undergoing variation, 00:32:20.870 --> 00:32:23.030 they have different effector functions 00:32:23.030 --> 00:32:26.420 and can do different things for the body. 00:32:26.420 --> 00:32:31.100 So for example, if you had isotype switching 00:32:31.100 --> 00:32:33.140 and you had a recombination event that 00:32:33.140 --> 00:32:37.160 brought this gamma 2 segment together with VDJ, 00:32:37.160 --> 00:32:41.940 that would produce the isotype which is known as IgG, 00:32:41.940 --> 00:32:47.060 and IgG is a highly secreted form of the antibody that 00:32:47.060 --> 00:32:50.930 is highly effective for bacterial infections 00:32:50.930 --> 00:32:53.180 because it's secreted in the blood, 00:32:53.180 --> 00:32:56.720 and it's able to neutralize bacteria and limit 00:32:56.720 --> 00:32:59.570 the infection that way. 00:32:59.570 --> 00:33:01.430 But there are other possibilities, 00:33:01.430 --> 00:33:04.610 because you have all of these different possibilities. 00:33:04.610 --> 00:33:08.630 And so you could get VDJ together with this alpha, 00:33:08.630 --> 00:33:13.300 and that would produce an isotype known as IgA. 00:33:13.300 --> 00:33:16.430 And IgA promotes mucosal immunity 00:33:16.430 --> 00:33:18.980 because it's able to pass through the epithelial linings. 00:33:21.890 --> 00:33:26.130 In addition, IgE is another type of antibody, 00:33:26.130 --> 00:33:29.900 and the constant domains are constant for each of isotypes, 00:33:29.900 --> 00:33:33.860 but they recruit different effector functions. 00:33:33.860 --> 00:33:41.630 So IgG would be hitting bacteria by promoting 00:33:41.630 --> 00:33:46.370 phagocytosis of those bacteria. 00:33:46.370 --> 00:33:51.150 IgE, in contrast, is especially good at dealing with worms, 00:33:51.150 --> 00:33:51.650 right? 00:33:51.650 --> 00:33:53.810 So if you have an intracellular-- 00:33:53.810 --> 00:33:57.530 or not intracellular, but like, an intestinal worm or something 00:33:57.530 --> 00:34:01.060 like that, then IgE-- 00:34:01.060 --> 00:34:04.970 its effector functions are better at dealing with that. 00:34:04.970 --> 00:34:08.120 So this process of isotype switching sort of 00:34:08.120 --> 00:34:12.139 allows the immune system to adapt to tackle 00:34:12.139 --> 00:34:16.980 a particular type of pathogen. 00:34:16.980 --> 00:34:17.480 All right. 00:34:17.480 --> 00:34:24.050 The last way in which T cells enhance this function 00:34:24.050 --> 00:34:28.070 is by promoting the differentiation of B cells 00:34:28.070 --> 00:34:30.139 into different types of B cells. 00:34:30.139 --> 00:34:34.480 One of those types of B cells is known as a memory B cell, 00:34:34.480 --> 00:34:37.190 and the memory B cell is a B cell 00:34:37.190 --> 00:34:39.710 that can last in the body for decades, 00:34:39.710 --> 00:34:44.000 even if the antigen is not present. 00:34:44.000 --> 00:34:49.250 So this mediates sort of the memory of the immune system. 00:34:49.250 --> 00:34:55.310 And so just to summarize what I just told you, 00:34:55.310 --> 00:34:59.000 if you have a B cell and it recognizes an antigen, which 00:34:59.000 --> 00:35:02.960 could be a protein, it would internalize that protein 00:35:02.960 --> 00:35:06.020 via endocytosis and then process it 00:35:06.020 --> 00:35:09.710 so that it can display peptides from that antigen 00:35:09.710 --> 00:35:11.240 on its surface. 00:35:11.240 --> 00:35:15.230 And if that's recognized by a T cell, 00:35:15.230 --> 00:35:18.440 then that leads to an interaction between the T and B 00:35:18.440 --> 00:35:22.080 cell that will lead to these different things happening, 00:35:22.080 --> 00:35:26.120 such as affinity maturation, isotype switching, 00:35:26.120 --> 00:35:29.060 so the red here would be a different constant chain 00:35:29.060 --> 00:35:31.860 on this same variable chain. 00:35:31.860 --> 00:35:34.340 So the variable chain doesn't change 00:35:34.340 --> 00:35:36.590 with the isotype switching, so it's still always 00:35:36.590 --> 00:35:38.530 able to recognize that antigen-- 00:35:38.530 --> 00:35:40.910 it's just recruiting different effector functions. 00:35:43.650 --> 00:35:46.190 And you can also get differentiation of B cells 00:35:46.190 --> 00:35:50.330 into plasma cells, which really secrete a ton of antibody, 00:35:50.330 --> 00:35:54.110 and therefore help the body fight infection. 00:35:54.110 --> 00:35:59.910 Now this is important because for a vaccine to be effective, 00:35:59.910 --> 00:36:03.530 you need to engage this T cell response such 00:36:03.530 --> 00:36:06.960 that you have all of these things happening. 00:36:06.960 --> 00:36:09.380 So all of these things need to happen 00:36:09.380 --> 00:36:11.960 for an effective vaccine. 00:36:16.610 --> 00:36:18.860 So for an effective vaccine, you can't just 00:36:18.860 --> 00:36:21.980 activate the humoral side of the immune system. 00:36:21.980 --> 00:36:24.230 You have to activate both the humoral 00:36:24.230 --> 00:36:27.920 and the cell-mediated sides such that they interact in order 00:36:27.920 --> 00:36:30.965 to enhance the immune response. 00:36:34.710 --> 00:36:35.210 All right. 00:36:35.210 --> 00:36:38.740 Now I'm going to move on and talk about a big problem 00:36:38.740 --> 00:36:41.230 that the immune system has, which 00:36:41.230 --> 00:36:44.410 is that it needs to somehow be able to discriminate 00:36:44.410 --> 00:36:48.700 between self and foreign, right? 00:36:48.700 --> 00:36:52.690 And so if you have your immune system recognizing 00:36:52.690 --> 00:36:56.170 an antigen that is natively part of your body, 00:36:56.170 --> 00:36:59.050 that results in an autoimmune disease. 00:36:59.050 --> 00:37:01.990 So there's a balance in the immune system 00:37:01.990 --> 00:37:07.930 between tolerating antigens or attacking them, 00:37:07.930 --> 00:37:11.860 and if it's attacking a native antigen, then it's autoimmune. 00:37:16.880 --> 00:37:18.380 And this is a huge problem because, 00:37:18.380 --> 00:37:21.920 if you think about it, because we've talked about the B cell 00:37:21.920 --> 00:37:25.100 receptor, the antibody, and the T cell receptor, right? 00:37:25.100 --> 00:37:28.010 Our bodies are generating tens of millions 00:37:28.010 --> 00:37:30.800 of these receptors that are diverse and can 00:37:30.800 --> 00:37:33.410 recognize different molecules. 00:37:33.410 --> 00:37:38.540 So our body is generating tens of millions 00:37:38.540 --> 00:37:46.770 of antigen receptors, and it does this constitutively, 00:37:46.770 --> 00:37:49.890 so that means that it's just doing it automatically. 00:37:49.890 --> 00:37:52.230 You don't even need to be infected for this to happen. 00:37:52.230 --> 00:37:56.730 This is just part of the development of B and T cells. 00:37:56.730 --> 00:38:00.860 OK, so it's constitutive, doesn't require infection-- 00:38:00.860 --> 00:38:01.710 constitutive. 00:38:04.400 --> 00:38:07.700 In addition, it's totally random. 00:38:07.700 --> 00:38:12.080 Your body could generate any sort of combination of V, Ds, 00:38:12.080 --> 00:38:15.200 and Js, and it could mutate in a certain way 00:38:15.200 --> 00:38:18.440 that it's likely that at some point during your lifetime 00:38:18.440 --> 00:38:20.930 you're going to generate a receptor that recognizes 00:38:20.930 --> 00:38:23.020 a native protein in your body. 00:38:23.020 --> 00:38:24.020 So it's totally random-- 00:38:26.930 --> 00:38:33.140 at least what the sort of rearrangement of VDJ gives. 00:38:33.140 --> 00:38:37.340 That process is constitutive and random. 00:38:37.340 --> 00:38:39.880 So I just want to point out several diseases that 00:38:39.880 --> 00:38:44.570 are caused by autoimmunity, and I've distinguished them 00:38:44.570 --> 00:38:47.810 based on whether the disease involves 00:38:47.810 --> 00:38:51.230 the generation of antibodies that recognize self or T 00:38:51.230 --> 00:38:53.840 cells that recognize self. 00:38:53.840 --> 00:38:58.370 So for antibodies, there's a disease, myasthenia gravis, 00:38:58.370 --> 00:39:01.640 which an individual's-- individuals generate 00:39:01.640 --> 00:39:05.930 an antibody against a receptor for a neurotransmitter, 00:39:05.930 --> 00:39:07.940 acetylcholine. 00:39:07.940 --> 00:39:10.670 And acetylcholine is the neurotransmitter 00:39:10.670 --> 00:39:14.570 which is predominantly involved in sending signals from a motor 00:39:14.570 --> 00:39:17.180 neuron to a muscle, and therefore 00:39:17.180 --> 00:39:19.820 antibodies that inhibit this receptor 00:39:19.820 --> 00:39:23.450 result in muscle weakness. 00:39:23.450 --> 00:39:27.140 Now self antibodies can also result in diabetes, 00:39:27.140 --> 00:39:29.270 and individuals can develop antibodies 00:39:29.270 --> 00:39:32.480 that recognize and inhibit the insulin receptor, 00:39:32.480 --> 00:39:36.440 and this leads to insulin resistance and diabetes 00:39:36.440 --> 00:39:39.020 mellitus. 00:39:39.020 --> 00:39:42.500 Some examples of T cell mediated diseases 00:39:42.500 --> 00:39:45.020 are-- if you recall back in the beginning of the month, 00:39:45.020 --> 00:39:48.320 when we talked about electrical signaling in neurons, 00:39:48.320 --> 00:39:50.870 I told you about the myelin sheath 00:39:50.870 --> 00:39:54.950 and how this increases the speed of the action 00:39:54.950 --> 00:39:58.370 potential along that axon. 00:39:58.370 --> 00:40:02.510 And if T cells attack the myelin sheath, 00:40:02.510 --> 00:40:06.820 then it disrupts this process of electrical signaling, 00:40:06.820 --> 00:40:09.170 and that results in a devastating disease, 00:40:09.170 --> 00:40:11.570 which is multiple sclerosis. 00:40:11.570 --> 00:40:16.680 Autoimmune disease involving T cells also involves diabetes, 00:40:16.680 --> 00:40:18.950 and if T cells attack and destroy 00:40:18.950 --> 00:40:23.720 the islet cells of the pancreas, this also 00:40:23.720 --> 00:40:26.780 disrupts the body's ability to produce insulin, 00:40:26.780 --> 00:40:30.260 and that results in type 1 diabetes. 00:40:30.260 --> 00:40:33.470 So I'm sure many of you know people 00:40:33.470 --> 00:40:37.970 with these types of diseases, and they're obviously 00:40:37.970 --> 00:40:41.600 of significant impact both in this country 00:40:41.600 --> 00:40:42.650 and around the world. 00:40:45.350 --> 00:40:49.520 So the problem for the cells in our body and the immune system 00:40:49.520 --> 00:40:54.050 is that the immune system has to have some sort of way 00:40:54.050 --> 00:40:57.590 to distinguish between self and foreign. 00:41:00.660 --> 00:41:04.760 So how is it that the immune system does this? 00:41:04.760 --> 00:41:07.490 And also, it has to have different responses 00:41:07.490 --> 00:41:10.760 to self-recognition versus foreign recognition. 00:41:13.820 --> 00:41:15.830 So what should the immune system's response 00:41:15.830 --> 00:41:20.950 be if there is a self recognition? 00:41:20.950 --> 00:41:22.600 What should it do to the cells that 00:41:22.600 --> 00:41:24.270 recognizes a native protein? 00:41:24.270 --> 00:41:25.173 Rachel? 00:41:25.173 --> 00:41:27.640 AUDIENCE: [INAUDIBLE] 00:41:27.640 --> 00:41:29.380 PROFESSOR: It could delete that cell. 00:41:29.380 --> 00:41:32.020 What Rachel said is you should get rid of it. 00:41:32.020 --> 00:41:36.220 And so one way to think about this process 00:41:36.220 --> 00:41:40.210 is there's a bit of a Darwinian natural selection going on 00:41:40.210 --> 00:41:43.960 in the body, and if there is a self recognition, 00:41:43.960 --> 00:41:48.370 then there should be a negative selection against that cell, 00:41:48.370 --> 00:41:50.410 so there should be negative selection. 00:41:50.410 --> 00:41:55.600 This cell should be more unfit, whereas if it's 00:41:55.600 --> 00:41:59.160 obviously foreign, then there should be positive selection. 00:41:59.160 --> 00:42:00.910 This B cell should be more fit. 00:42:05.170 --> 00:42:07.690 And what Rachel suggested is to get rid 00:42:07.690 --> 00:42:10.480 of the cell, which is a great idea, because if you kill off 00:42:10.480 --> 00:42:13.750 the cell then you won't generate any more cells that have 00:42:13.750 --> 00:42:16.210 that recognition against self. 00:42:16.210 --> 00:42:21.110 So negative selection is mediated by apoptosis and cell 00:42:21.110 --> 00:42:21.610 death. 00:42:26.710 --> 00:42:30.760 And positive selection could be both the activation of the cell 00:42:30.760 --> 00:42:32.740 and also its proliferation. 00:42:32.740 --> 00:42:36.240 As you see up on the slide there, that orange cell-- 00:42:36.240 --> 00:42:40.260 if it was recognizing a foreign antigen, would get activated 00:42:40.260 --> 00:42:43.720 and it would undergo a monoclonal expansion. 00:42:43.720 --> 00:42:46.450 All the cells resulting from that expansion 00:42:46.450 --> 00:42:49.420 would express the same antibody and therefore recognize 00:42:49.420 --> 00:42:52.750 that antigen, so this would result 00:42:52.750 --> 00:42:59.650 in cell division or expansion of that population of cell. 00:43:06.420 --> 00:43:12.380 So now we know what to do with self versus foreign, 00:43:12.380 --> 00:43:14.420 but how is it that we distinguish 00:43:14.420 --> 00:43:16.640 between self and foreign? 00:43:16.640 --> 00:43:29.480 So how does the immune system distinguish self from foreign? 00:43:29.480 --> 00:43:33.570 And there are several mechanisms to do this. 00:43:33.570 --> 00:43:37.820 The first is that the organs-- 00:43:37.820 --> 00:43:40.850 the lymphoid organs-- where are these B and T cells 00:43:40.850 --> 00:43:44.720 mature and undergo these genomic rearrangements 00:43:44.720 --> 00:43:47.315 are largely protected from foreign agents. 00:43:49.910 --> 00:43:58.760 So there are basically only self antigens 00:43:58.760 --> 00:44:02.645 in the generative lymphoid organs. 00:44:06.770 --> 00:44:09.050 These are the lymphoid organs were B and T 00:44:09.050 --> 00:44:10.340 cells are being generated. 00:44:13.340 --> 00:44:15.440 So the generative lymphoid organs 00:44:15.440 --> 00:44:21.830 would be the bone marrow for B cells 00:44:21.830 --> 00:44:23.330 and the thymus for T cells. 00:44:26.090 --> 00:44:29.150 Therefore, if a B or T cell-- 00:44:29.150 --> 00:44:31.430 if its receptor engages with something 00:44:31.430 --> 00:44:33.950 very tightly during its development, 00:44:33.950 --> 00:44:36.950 that's a signal for the immune system 00:44:36.950 --> 00:44:39.020 to delete and kill off that cell. 00:44:43.430 --> 00:44:46.100 So if you get self recognition here, 00:44:46.100 --> 00:44:50.310 you get apoptosis and deletion of that cell. 00:44:50.310 --> 00:44:54.470 The second way that the body is able to distinguish 00:44:54.470 --> 00:45:01.160 is that it responds to antigens specifically 00:45:01.160 --> 00:45:04.022 when there is an innate immune response, 00:45:04.022 --> 00:45:05.480 or if it responds better when there 00:45:05.480 --> 00:45:07.075 is an innate immune response. 00:45:13.410 --> 00:45:17.540 So you can think of it like a coincidence detector, right? 00:45:17.540 --> 00:45:21.380 If you have an immune cell and it recognizes an antigen, 00:45:21.380 --> 00:45:24.080 and there's also an innate immune response, 00:45:24.080 --> 00:45:28.880 that's a strong indication that this is foreign. 00:45:28.880 --> 00:45:31.700 So this would indicate "foreign" to the immune system. 00:45:35.350 --> 00:45:40.010 If there is antigen only and the body is not 00:45:40.010 --> 00:45:42.830 mounting an innate immune response, 00:45:42.830 --> 00:45:46.760 it's much more likely that this will generate 00:45:46.760 --> 00:45:51.020 a robust immune response, and this is the immune system's 00:45:51.020 --> 00:45:57.260 signal that this is a self antigen. 00:45:57.260 --> 00:46:00.530 This is also important for vaccine development 00:46:00.530 --> 00:46:02.600 because in most vaccines, in addition 00:46:02.600 --> 00:46:07.990 to having some antigen that's a part of the infectious agent, 00:46:07.990 --> 00:46:14.060 there's also something called an adjuvant, which is basically 00:46:14.060 --> 00:46:18.500 something that activates the innate immune system. 00:46:18.500 --> 00:46:22.940 So the adjuvant activates the innate immune response, 00:46:22.940 --> 00:46:25.700 and that's important because if you just 00:46:25.700 --> 00:46:27.890 had the vaccine with just the antigen, 00:46:27.890 --> 00:46:31.550 there wouldn't be nearly as robust a response. 00:46:31.550 --> 00:46:37.490 So you need both to activate the adaptive immune system, 00:46:37.490 --> 00:46:40.460 but also the innate immune system to really get 00:46:40.460 --> 00:46:41.810 a robust response. 00:46:46.130 --> 00:46:50.180 So I want to end by talking about this year's Nobel Prize 00:46:50.180 --> 00:46:56.330 work, and it involves another mechanism that 00:46:56.330 --> 00:46:59.960 basically prevents autoimmunity and downregulates 00:46:59.960 --> 00:47:06.890 the activity of these T cells, and that 00:47:06.890 --> 00:47:09.920 involves another type of-- we've only talked about activating 00:47:09.920 --> 00:47:11.300 receptors on the T cell, right? 00:47:11.300 --> 00:47:14.450 The T cell receptor, CD4, CD8-- 00:47:14.450 --> 00:47:17.820 they're activating receptors for the T cell receptor, 00:47:17.820 --> 00:47:21.500 but there are also inhibitory receptors that 00:47:21.500 --> 00:47:24.000 are on the surface of T cells. 00:47:24.000 --> 00:47:27.830 So inhibitory-- we'll just call them receptors. 00:47:27.830 --> 00:47:33.260 One is called CTLA4 and another is called PD1. 00:47:37.790 --> 00:47:41.180 Their names are not terribly important, but what they do 00:47:41.180 --> 00:47:44.870 is they keep the immune system in check. 00:47:44.870 --> 00:47:46.670 And we've talked a lot about signaling 00:47:46.670 --> 00:47:49.310 and how signaling gets activated, 00:47:49.310 --> 00:47:53.600 and often a step in signaling is once you get the signal sent, 00:47:53.600 --> 00:47:57.080 and it's been sent, there is, like, a negative feedback 00:47:57.080 --> 00:47:59.390 that then turns off the signal such 00:47:59.390 --> 00:48:02.030 that there's signal termination. 00:48:02.030 --> 00:48:04.850 So you often have some type of signal termination. 00:48:08.000 --> 00:48:11.150 That way, you don't have just a constitutive activation 00:48:11.150 --> 00:48:13.250 of the signal, which in this case 00:48:13.250 --> 00:48:16.760 would be sort of inflammation and an immune response, 00:48:16.760 --> 00:48:20.300 and one or both of these is involved 00:48:20.300 --> 00:48:22.460 in sort of keeping the immune system in check 00:48:22.460 --> 00:48:27.740 and stopping it after you get that initial reaction. 00:48:27.740 --> 00:48:29.830 Now, the reason this is so important 00:48:29.830 --> 00:48:34.280 and why James Allison and Tasuku Honjo won 00:48:34.280 --> 00:48:36.590 the Nobel Prize is they had the idea 00:48:36.590 --> 00:48:41.750 to use this as a therapy for cancer. 00:48:41.750 --> 00:48:45.380 And it turns out that some cancer cells 00:48:45.380 --> 00:48:51.620 can express the ligand for these inhibitory receptors 00:48:51.620 --> 00:48:54.830 such that they can avoid the immune system from recognizing 00:48:54.830 --> 00:48:56.510 the tumor. 00:48:56.510 --> 00:49:01.220 So this would be one case where the tumor cell is expressing 00:49:01.220 --> 00:49:05.570 the ligand for PD1, and that inhibits the function of this T 00:49:05.570 --> 00:49:09.140 cell receptor so that it doesn't kill the tumor cell, 00:49:09.140 --> 00:49:13.080 and that leads to the expansion of the tumor 00:49:13.080 --> 00:49:17.300 so the tumor can expand in an unchecked way. 00:49:17.300 --> 00:49:22.070 And what James Allison and Tasuku Honjo determined 00:49:22.070 --> 00:49:27.050 is that if you block that inhibitory receptor, 00:49:27.050 --> 00:49:31.340 then you sort of uncheck the response of the immune system 00:49:31.340 --> 00:49:33.260 such that these immune cells are now 00:49:33.260 --> 00:49:37.700 able to recognize the tumor cells and kill them. 00:49:37.700 --> 00:49:41.780 So by sort of blocking the inhibitor, 00:49:41.780 --> 00:49:45.860 you now have T cells-- these are CD8 positive T cells that are 00:49:45.860 --> 00:49:47.060 killer cells-- 00:49:47.060 --> 00:49:50.120 they will now recognize these T cells and kill them off. 00:49:52.940 --> 00:49:58.550 So there's what's known as an inhibitor blockade 00:49:58.550 --> 00:50:05.570 because you're blocking the inhibitor, 00:50:05.570 --> 00:50:10.340 and these inhibitors are antibodies that recognize 00:50:10.340 --> 00:50:14.960 these inhibitory receptors, and they're now being used to treat 00:50:14.960 --> 00:50:19.250 some forms of advanced cancer. 00:50:19.250 --> 00:50:21.410 And so this is something that the cancer 00:50:21.410 --> 00:50:25.580 field and immunology fields are both really excited about. 00:50:25.580 --> 00:50:31.130 What might be one complication with this type of treatment? 00:50:31.130 --> 00:50:33.290 If you get rid of the inhibitory receptors, 00:50:33.290 --> 00:50:35.590 what might be a consequence? 00:50:35.590 --> 00:50:36.330 Yeah, Steven? 00:50:36.330 --> 00:50:38.665 AUDIENCE: Then you could recognize other self cells that 00:50:38.665 --> 00:50:40.070 inhibited [INAUDIBLE]. 00:50:40.070 --> 00:50:42.080 PROFESSOR: Yeah, you get autoimmunity. 00:50:42.080 --> 00:50:43.250 That's exactly right. 00:50:43.250 --> 00:50:46.580 So one of the downsides of this is that-- 00:50:46.580 --> 00:50:49.310 one of the side effects is that you can have patients 00:50:49.310 --> 00:50:51.690 with an autoimmune reaction. 00:50:51.690 --> 00:50:53.900 So it's not the magic bullet, but it's 00:50:53.900 --> 00:50:55.880 a step in the right direction. 00:50:55.880 --> 00:50:58.840 All right, we'll see you next week.