1 00:00:16,865 --> 00:00:17,740 PROFESSOR: All right. 2 00:00:17,740 --> 00:00:21,710 So today, we're going to talk about immunity again. 3 00:00:21,710 --> 00:00:27,100 And so this movie up on the screen here-- 4 00:00:27,100 --> 00:00:28,330 this is a cell. 5 00:00:28,330 --> 00:00:31,705 You can see the outline of the cells kind of around here. 6 00:00:31,705 --> 00:00:33,933 That's the outline of the cell. 7 00:00:33,933 --> 00:00:35,350 But what you can see is that there 8 00:00:35,350 --> 00:00:38,740 is something in the cell moving around, 9 00:00:38,740 --> 00:00:43,450 and that is an intracellular bacteria called listeria. 10 00:00:43,450 --> 00:00:47,020 And you can see it's rocketing around in this cell. 11 00:00:47,020 --> 00:00:50,110 It's having a total party in this cell, 12 00:00:50,110 --> 00:00:56,110 and what you'll see here is you can often see the bacteria push 13 00:00:56,110 --> 00:00:57,753 out from the cell. 14 00:00:57,753 --> 00:00:59,920 So if you look here, one is going to push right now. 15 00:00:59,920 --> 00:01:00,580 See? 16 00:01:00,580 --> 00:01:01,163 There it goes. 17 00:01:01,163 --> 00:01:03,520 And it kind of runs into the edge of the cell 18 00:01:03,520 --> 00:01:08,380 and pushes out, and this enables the bacteria 19 00:01:08,380 --> 00:01:11,950 to spread from cell to cell without actually going 20 00:01:11,950 --> 00:01:15,790 into the extracellular space surrounding the cells, OK? 21 00:01:18,660 --> 00:01:21,390 So let's take a hypothetical situation. 22 00:01:24,720 --> 00:01:27,360 So listeria is a foodborne illness. 23 00:01:27,360 --> 00:01:33,570 It causes a nasty sort of intestinal disease. 24 00:01:33,570 --> 00:01:38,490 So Brett, do you want these bacteria having 25 00:01:38,490 --> 00:01:39,600 a party in your cells? 26 00:01:39,600 --> 00:01:40,950 AUDIENCE: Unlikely. 27 00:01:40,950 --> 00:01:42,010 PROFESSOR: Hell no. 28 00:01:42,010 --> 00:01:46,710 OK, Malik, do you want these bacteria having 29 00:01:46,710 --> 00:01:48,840 a party in your cells? 30 00:01:48,840 --> 00:01:50,010 Hell no. 31 00:01:50,010 --> 00:01:52,890 Carmen, do you want these bacteria 32 00:01:52,890 --> 00:01:54,390 having a party in your cells? 33 00:01:54,390 --> 00:01:55,230 AUDIENCE: Hell no. 34 00:01:55,230 --> 00:01:56,140 PROFESSOR: Hell no! 35 00:01:56,140 --> 00:01:56,640 Yes. 36 00:01:56,640 --> 00:02:02,310 OK, so our body has to have some way to sort of address 37 00:02:02,310 --> 00:02:06,030 this type of an illness, and the problem 38 00:02:06,030 --> 00:02:11,440 is if you're thinking about what we discussed on Wednesday, is-- 39 00:02:11,440 --> 00:02:11,940 all right. 40 00:02:11,940 --> 00:02:14,220 So you're hosting this party, right? 41 00:02:14,220 --> 00:02:15,840 This is your cell. 42 00:02:15,840 --> 00:02:17,670 So you have a host cell-- 43 00:02:17,670 --> 00:02:24,000 that's your cell-- and you have an intracellular pathogen, 44 00:02:24,000 --> 00:02:27,360 such as a bacteria or it could also be a virus, 45 00:02:27,360 --> 00:02:30,660 and they're essentially using your generous host 46 00:02:30,660 --> 00:02:33,240 cell to reproduce itself to spread 47 00:02:33,240 --> 00:02:35,790 to other cells of the body. 48 00:02:35,790 --> 00:02:39,330 And so you don't want that, but the problem is that-- 49 00:02:39,330 --> 00:02:44,070 I told you about B cells, so remember B cells-- 50 00:02:44,070 --> 00:02:46,740 they have an antigen receptor. 51 00:02:46,740 --> 00:02:50,520 It's initially on their plasma membrane. 52 00:02:50,520 --> 00:02:55,740 It can also be secreted, and it's secreted 53 00:02:55,740 --> 00:02:58,030 into the extracellular space. 54 00:02:58,030 --> 00:03:02,410 The problem is that these pathogens are inside the cell, 55 00:03:02,410 --> 00:03:05,700 and there's a plasma membrane separating them 56 00:03:05,700 --> 00:03:10,950 from the antigen receptors that you need to recognize them, OK? 57 00:03:10,950 --> 00:03:14,050 So this presents an issue. 58 00:03:14,050 --> 00:03:18,270 It's also the case for T cells, because as you heard 59 00:03:18,270 --> 00:03:22,440 on Wednesday, T cells only have this membrane-bound form 60 00:03:22,440 --> 00:03:27,900 of the receptor, and the antigen recognition domains of all 61 00:03:27,900 --> 00:03:32,640 of these are extracellular, so there is really-- 62 00:03:32,640 --> 00:03:36,390 with just this system, there's no way for your immune cells 63 00:03:36,390 --> 00:03:38,490 to see in the cells. 64 00:03:38,490 --> 00:03:40,650 So today, I want to talk about how 65 00:03:40,650 --> 00:03:44,040 is it that the immune cells are able-- 66 00:03:44,040 --> 00:03:47,460 how our immune cells are able to see within the cell 67 00:03:47,460 --> 00:03:53,340 in order to address an infection like this one, with listeria. 68 00:03:53,340 --> 00:03:54,480 OK? 69 00:03:54,480 --> 00:03:57,180 And the first part of the answer is 70 00:03:57,180 --> 00:04:01,610 that it involves a process known as antigen presentation. 71 00:04:09,870 --> 00:04:13,640 And antigen presentation is the process 72 00:04:13,640 --> 00:04:21,140 by which peptides, so short sequences of amino acids, 73 00:04:21,140 --> 00:04:25,250 are presented and displayed on the surface of the cell 74 00:04:25,250 --> 00:04:26,990 for the immune system-- 75 00:04:26,990 --> 00:04:28,580 for immune cells to see. 76 00:04:28,580 --> 00:04:50,080 So here, peptides are displayed on the cell surface 77 00:04:50,080 --> 00:04:51,730 for immune cells to see them. 78 00:04:51,730 --> 00:04:55,810 And in this specific case, it's going to be for the T cells 79 00:04:55,810 --> 00:05:00,060 to observe what's going on inside the cell, OK? 80 00:05:03,040 --> 00:05:07,360 So this mechanism involves another molecule, 81 00:05:07,360 --> 00:05:09,840 which I briefly introduced. 82 00:05:09,840 --> 00:05:21,280 It's called the major histocompatibility complex, 83 00:05:21,280 --> 00:05:24,070 which is abbreviated MHC. 84 00:05:24,070 --> 00:05:28,420 So when I referred to MHC in Wednesday's lecture, 85 00:05:28,420 --> 00:05:31,810 I was referring to this major histocompatibility complex. 86 00:05:34,550 --> 00:05:38,920 And there are two classes of MHCs. 87 00:05:38,920 --> 00:05:43,620 Thankfully, the first one is known as class 1, 88 00:05:43,620 --> 00:05:52,600 so class 1 MHC, and class 1 MHC looks like this. 89 00:05:52,600 --> 00:05:55,810 Like many of the immune receptors 90 00:05:55,810 --> 00:06:00,250 that I've talked about, it has a heavy chain, 91 00:06:00,250 --> 00:06:04,150 which is this long polypeptide light blue, 92 00:06:04,150 --> 00:06:07,630 and it has a light chain in purple. 93 00:06:07,630 --> 00:06:12,430 So the MHC is composed of these two separate polypeptides. 94 00:06:12,430 --> 00:06:14,830 They're encoded by different genes, 95 00:06:14,830 --> 00:06:19,100 and then it assembles into this structure shown here. 96 00:06:19,100 --> 00:06:22,720 So this molecule has two Ig domains, 97 00:06:22,720 --> 00:06:26,450 and these are proximal to the plasma membrane. 98 00:06:26,450 --> 00:06:28,850 And this thing is all inserted in the plasma membrane. 99 00:06:28,850 --> 00:06:31,780 It's an integral membrane protein. 100 00:06:31,780 --> 00:06:34,780 And then distal to the plasma membrane 101 00:06:34,780 --> 00:06:37,390 is this structure here, and if you 102 00:06:37,390 --> 00:06:40,330 look at the crystal structure, it's kind of like a sheet-- 103 00:06:40,330 --> 00:06:44,710 a beta sheet with two alpha helices. 104 00:06:44,710 --> 00:06:48,130 And altogether what it does is it basically creates, 105 00:06:48,130 --> 00:06:50,890 like, a little cup, OK? 106 00:06:50,890 --> 00:06:53,590 So it's creating, like, a cup. 107 00:06:53,590 --> 00:06:58,690 And what sits in this cup is a peptide, so you get peptides, 108 00:06:58,690 --> 00:07:02,560 and the peptides sort of sit in that hand, if you will. 109 00:07:02,560 --> 00:07:06,540 And some of the amino acids from that peptide are sticking out 110 00:07:06,540 --> 00:07:10,750 and they're sort of displayed away from the MHC molecule. 111 00:07:13,780 --> 00:07:18,700 So this is basically a hand that holds peptides and displays 112 00:07:18,700 --> 00:07:23,440 them on the outside of the cell, right? 113 00:07:23,440 --> 00:07:25,990 So the outside of the cell here is up. 114 00:07:25,990 --> 00:07:28,300 This would be the exoplasm out here, 115 00:07:28,300 --> 00:07:31,090 and it's displaying these peptides for immune cells 116 00:07:31,090 --> 00:07:32,575 like T cells to observe. 117 00:07:36,840 --> 00:07:37,340 All right. 118 00:07:37,340 --> 00:07:41,660 So class 1 MHC is a class that's expressed 119 00:07:41,660 --> 00:07:48,350 on all nucleated cells in your body. 120 00:07:51,530 --> 00:07:54,320 So that's all of your nucleotide cells 121 00:07:54,320 --> 00:07:58,370 are synthesizing in a class 1 MHC, 122 00:07:58,370 --> 00:08:02,660 and then it's sort of being displayed on the surface. 123 00:08:02,660 --> 00:08:06,470 And the peptides that are held by this class 1 MHC-- 124 00:08:09,630 --> 00:08:12,620 the peptides here are being derived 125 00:08:12,620 --> 00:08:17,720 from a specific place in the cell, which is the cytoplasm. 126 00:08:17,720 --> 00:08:21,990 So the peptides are from the cytoplasm, 127 00:08:21,990 --> 00:08:27,170 so this is the source of the peptides, 128 00:08:27,170 --> 00:08:31,610 and I'll tell you how these peptides are sort of loaded 129 00:08:31,610 --> 00:08:34,890 on to this MHC molecule. 130 00:08:34,890 --> 00:08:39,919 So the MHC molecule is a membrane protein, 131 00:08:39,919 --> 00:08:45,050 so it's translated on the endoplasmic reticulum, 132 00:08:45,050 --> 00:08:47,780 and its extracellular domain is initially 133 00:08:47,780 --> 00:08:51,170 present in the lumen of the ER. 134 00:08:51,170 --> 00:08:53,150 And the peptides are from proteins 135 00:08:53,150 --> 00:08:55,520 that are present in the cytoplasm, 136 00:08:55,520 --> 00:08:57,920 and what happens to these proteins-- 137 00:08:57,920 --> 00:09:01,890 and this occurs for unfolded proteins, 138 00:09:01,890 --> 00:09:05,150 but also for proteins that might be ubiquitinated-- 139 00:09:05,150 --> 00:09:08,420 is that they're processed by the proteasome, which 140 00:09:08,420 --> 00:09:14,990 is this kind of a shredder-like function for proteins, 141 00:09:14,990 --> 00:09:20,300 and it cuts up the proteins into little snippets, or peptides, 142 00:09:20,300 --> 00:09:23,960 that can then be pumped into the lumen of the ER 143 00:09:23,960 --> 00:09:26,000 through this transporter, TAP. 144 00:09:26,000 --> 00:09:28,970 So these peptides can be taken and transported 145 00:09:28,970 --> 00:09:31,340 into the lumen of the ER, and that's 146 00:09:31,340 --> 00:09:35,570 where they're loaded onto the class 1 MHC molecule. 147 00:09:35,570 --> 00:09:38,570 But the source peptides is from proteins 148 00:09:38,570 --> 00:09:40,100 that are in the cytoplasm. 149 00:09:40,100 --> 00:09:43,520 They're processed by the proteasome. 150 00:09:43,520 --> 00:09:47,390 So then, once you have a peptide-MHC complex, 151 00:09:47,390 --> 00:09:50,090 it can then be trafficked through the normal vesicle 152 00:09:50,090 --> 00:09:53,780 trafficking pathway all the way out to the plasma membrane 153 00:09:53,780 --> 00:09:57,440 of the cell where now that peptide will be displayed 154 00:09:57,440 --> 00:10:00,040 for T cells to observe. 155 00:10:03,110 --> 00:10:05,180 And so the peptides here, they're 156 00:10:05,180 --> 00:10:09,470 processed by the proteasome-- 157 00:10:09,470 --> 00:10:13,670 processed or cut by the proteasome-- 158 00:10:19,010 --> 00:10:21,440 and then the type of T cell that's 159 00:10:21,440 --> 00:10:25,190 going to look at these class 1 molecules-- 160 00:10:25,190 --> 00:10:28,970 they are known as seeds CD8 positive T cells. 161 00:10:33,080 --> 00:10:37,350 So this is the first class of MHC molecule. 162 00:10:37,350 --> 00:10:39,170 Because there is a class 1, that means 163 00:10:39,170 --> 00:10:42,740 there also must be a class 2, which there is. 164 00:10:42,740 --> 00:10:49,730 And so class 2 MHCs are fundamentally different in all 165 00:10:49,730 --> 00:10:50,840 of these properties. 166 00:10:53,990 --> 00:10:58,310 The function shared by these MHC molecules 167 00:10:58,310 --> 00:11:02,670 is they both display peptides on the surface of the cell. 168 00:11:02,670 --> 00:11:08,660 So MHC molecules do display peptides 169 00:11:08,660 --> 00:11:13,190 on the surface, which is known as antigen presentation. 170 00:11:13,190 --> 00:11:18,320 But other than that, MHC class 2 is pretty different. 171 00:11:18,320 --> 00:11:21,170 You see the structure of MHC class 2 172 00:11:21,170 --> 00:11:24,920 is very similar to that of class 1, 173 00:11:24,920 --> 00:11:27,080 but you see that rather than having 174 00:11:27,080 --> 00:11:29,030 a heavy and a light chain, here there 175 00:11:29,030 --> 00:11:33,320 are two chains that are roughly of equal size. 176 00:11:33,320 --> 00:11:36,550 And so these are encoded by different genes 177 00:11:36,550 --> 00:11:42,350 than the class 1 molecule, and they encode different proteins. 178 00:11:42,350 --> 00:11:47,760 But the overall structural similarity is very similar, 179 00:11:47,760 --> 00:11:49,640 so there are two Ig domains, they're 180 00:11:49,640 --> 00:11:52,910 proximal to the plasma membrane, and then there's 181 00:11:52,910 --> 00:11:58,250 this structure at the very end of the MHC molecule, 182 00:11:58,250 --> 00:12:00,560 which has this groove in it which 183 00:12:00,560 --> 00:12:03,110 can hold a peptide that would be displayed 184 00:12:03,110 --> 00:12:06,390 on the surface of the cell. 185 00:12:06,390 --> 00:12:09,410 And there, you see the groove and you see the peptide 186 00:12:09,410 --> 00:12:12,610 that is present in it. 187 00:12:12,610 --> 00:12:18,170 All right, so one big difference between class 1 and class 2 188 00:12:18,170 --> 00:12:22,640 is that class 2 is expressed on a much more restricted set 189 00:12:22,640 --> 00:12:23,990 of cells. 190 00:12:23,990 --> 00:12:29,030 So class 2 MHCs are expressed specifically on specialized 191 00:12:29,030 --> 00:12:38,120 cells known as antigen-presenting cells, 192 00:12:38,120 --> 00:12:43,040 and these antigen presenting cells include cells like B 193 00:12:43,040 --> 00:12:48,230 cells, which are the ones that I'll focus on, but also 194 00:12:48,230 --> 00:12:53,300 phagocytic that can phagocytose foreign substances-- 195 00:12:58,390 --> 00:13:04,280 phagocytic cells-- and there's another cell type 196 00:13:04,280 --> 00:13:06,500 called the dendritic cell, which is also 197 00:13:06,500 --> 00:13:08,270 an antigen-presenting cell. 198 00:13:08,270 --> 00:13:10,880 I'm going to focus on the B cells. 199 00:13:10,880 --> 00:13:13,730 So class 1 is expressed everywhere. 200 00:13:13,730 --> 00:13:16,760 Class 2 is really expressed on these professional 201 00:13:16,760 --> 00:13:18,290 antigen-presenting cells. 202 00:13:20,958 --> 00:13:23,660 And the way that the peptides-- 203 00:13:23,660 --> 00:13:26,960 the source of the peptides and the way they're generated 204 00:13:26,960 --> 00:13:29,270 is also very different. 205 00:13:29,270 --> 00:13:37,700 So peptides for class 2 come from the extracellular space, 206 00:13:37,700 --> 00:13:42,020 and they are processed by lysosomal proteases. 207 00:13:53,190 --> 00:13:56,720 And so I'll show you how that looks in cartoon form. 208 00:13:59,550 --> 00:14:02,810 So for MHC class 2, the peptides are 209 00:14:02,810 --> 00:14:05,420 from the extracellular space. 210 00:14:05,420 --> 00:14:09,590 And so we've talked about ways that cells 211 00:14:09,590 --> 00:14:11,030 can take in material. 212 00:14:11,030 --> 00:14:13,400 One way is through endocytosis, right? 213 00:14:13,400 --> 00:14:15,950 So if this is my antigen, the antigen 214 00:14:15,950 --> 00:14:20,600 could be endocytosed by the cell, 215 00:14:20,600 --> 00:14:26,300 and now it's in a vesicle that's present in the cell. 216 00:14:26,300 --> 00:14:29,360 And so if you endocytose this protein, 217 00:14:29,360 --> 00:14:33,500 then it's now in a vesicle, and one compartment 218 00:14:33,500 --> 00:14:35,660 that it can go to is the lysosome, 219 00:14:35,660 --> 00:14:38,840 where are these there are these lysosomal proteases they 220 00:14:38,840 --> 00:14:41,840 can then chop up this protein into little snippets, 221 00:14:41,840 --> 00:14:44,370 or peptides. 222 00:14:44,370 --> 00:14:48,140 And so MHC class 2, again, is translated 223 00:14:48,140 --> 00:14:49,820 at the end of endoplasmic reticulum, 224 00:14:49,820 --> 00:14:51,815 like all plasma membrane proteins. 225 00:14:55,430 --> 00:14:57,470 But in the endoplasmic reticulum, 226 00:14:57,470 --> 00:15:00,740 you see the peptide groove is blocked such 227 00:15:00,740 --> 00:15:03,770 that peptides derived from the cytoplasm 228 00:15:03,770 --> 00:15:07,490 can't interact with class 2, but then 229 00:15:07,490 --> 00:15:11,870 is trafficked to a unique compartment which can combine 230 00:15:11,870 --> 00:15:16,100 with the compartment that has the peptides that originated 231 00:15:16,100 --> 00:15:17,990 from outside the cell. 232 00:15:17,990 --> 00:15:22,700 And then those can get loaded onto this class 2 MHC molecule, 233 00:15:22,700 --> 00:15:25,970 and then this can be recognized by T cells. 234 00:15:25,970 --> 00:15:28,884 But in this case, it is a-- 235 00:15:28,884 --> 00:15:30,980 oh, I endocytosed my chalk. 236 00:15:30,980 --> 00:15:32,230 I need to get it back. 237 00:15:32,230 --> 00:15:33,110 Here. 238 00:15:33,110 --> 00:15:38,630 So in this case, it's not a CD8 T cell that's recognizing it, 239 00:15:38,630 --> 00:15:40,670 but a CD4 positive T cell. 240 00:15:45,150 --> 00:15:49,640 OK, so let me briefly review what I just went through, 241 00:15:49,640 --> 00:15:53,840 and review the differences between class 1 and class 2. 242 00:15:53,840 --> 00:15:58,010 So class 1 MHC is expressed on all nucleated cells, 243 00:15:58,010 --> 00:16:00,290 whereas class 2 is much more restricted, 244 00:16:00,290 --> 00:16:04,385 being expressed specifically on antigen-presenting cells. 245 00:16:07,100 --> 00:16:10,940 The T cells that recognize these two classes are different. 246 00:16:10,940 --> 00:16:14,570 Class 1's recognized by CD8 positive T cells. 247 00:16:14,570 --> 00:16:20,060 Class 2 is recognized by CD4 positive T cells. 248 00:16:20,060 --> 00:16:24,570 And the source of the antigen is different in these two cases. 249 00:16:24,570 --> 00:16:27,980 The source of the antigen for class 1 is the cytoplasm. 250 00:16:27,980 --> 00:16:32,090 For class 2, it's the extracellular space. 251 00:16:32,090 --> 00:16:35,030 So the different MHCs are sampling different sort 252 00:16:35,030 --> 00:16:38,330 of pools of proteins. 253 00:16:38,330 --> 00:16:40,820 And where the peptide is loaded is 254 00:16:40,820 --> 00:16:42,680 distinct between these two, which 255 00:16:42,680 --> 00:16:45,680 allows these distinct classes to basically 256 00:16:45,680 --> 00:16:48,500 discriminate between the sources of the peptides 257 00:16:48,500 --> 00:16:50,090 that they're loading. 258 00:16:50,090 --> 00:16:52,280 So for class 1, that's in the ER. 259 00:16:52,280 --> 00:16:56,600 For class 2, it arises from a vesicle compartment 260 00:16:56,600 --> 00:17:00,380 that results from endocytosis of an antigen 261 00:17:00,380 --> 00:17:01,670 from outside the cell. 262 00:17:06,869 --> 00:17:07,440 All right. 263 00:17:07,440 --> 00:17:11,640 Now, the type of molecule that recognizes this MHC 264 00:17:11,640 --> 00:17:18,950 peptide complex is the T cell receptor, which I briefly 265 00:17:18,950 --> 00:17:21,290 outlined on Wednesday, but now we're 266 00:17:21,290 --> 00:17:24,290 going to talk about it in much more detail. 267 00:17:24,290 --> 00:17:30,180 So the T cell receptor, or TCR-- 268 00:17:30,180 --> 00:17:34,250 and I talked about its structure which is shown up on the slide, 269 00:17:34,250 --> 00:17:36,620 but I'll just draw more simply here. 270 00:17:36,620 --> 00:17:41,070 If this is the plasma membrane, this is the cytoplasm, 271 00:17:41,070 --> 00:17:44,900 and this is the exoplasm facing down, 272 00:17:44,900 --> 00:17:48,200 then this T cell receptor has two chains. 273 00:17:48,200 --> 00:17:52,370 One is called the alpha chain, and the second 274 00:17:52,370 --> 00:17:53,495 is called the beta chain. 275 00:17:56,390 --> 00:18:00,590 And each is comprised of two Ig domains, 276 00:18:00,590 --> 00:18:02,930 which you see up there. 277 00:18:02,930 --> 00:18:06,830 So the T cell receptor here is in pink. 278 00:18:06,830 --> 00:18:09,740 You can see an Ig domain there on one strand-- 279 00:18:09,740 --> 00:18:11,990 Ig domain there. 280 00:18:11,990 --> 00:18:18,650 And you have another two Ig domains on the other subunit, 281 00:18:18,650 --> 00:18:21,800 and this receptor, the T cell receptor, 282 00:18:21,800 --> 00:18:27,470 recognizes antigens through its variable domain, which is here. 283 00:18:27,470 --> 00:18:31,580 And it's binding basically to the end of this receptor, 284 00:18:31,580 --> 00:18:35,990 so this is a sort of ribbon diagram of a structure for a T 285 00:18:35,990 --> 00:18:37,040 cell receptor. 286 00:18:37,040 --> 00:18:39,270 The plasma membrane would be up here. 287 00:18:39,270 --> 00:18:41,930 This is the end of the T cell receptor. 288 00:18:41,930 --> 00:18:45,740 And MHC is in green, and it's holding a peptide here 289 00:18:45,740 --> 00:18:47,100 in yellow. 290 00:18:47,100 --> 00:18:52,190 And you can see how the TCR is sort of interacting or docking 291 00:18:52,190 --> 00:18:54,290 to this MHC-peptide complex. 292 00:18:57,380 --> 00:19:04,920 So for the T cell receptor to interact and bind to MHC, 293 00:19:04,920 --> 00:19:07,070 you have to have a T cell receptor that 294 00:19:07,070 --> 00:19:09,290 recognizes the specific conformation 295 00:19:09,290 --> 00:19:12,830 of the peptide that is being sort of extended away 296 00:19:12,830 --> 00:19:14,480 from the cell. 297 00:19:14,480 --> 00:19:17,510 So let's say this is my T cell receptor, 298 00:19:17,510 --> 00:19:20,210 and I'm going around and searching for cells that 299 00:19:20,210 --> 00:19:22,100 might want to look at this. 300 00:19:22,100 --> 00:19:25,880 Then if I had a T cell receptor that was like this, 301 00:19:25,880 --> 00:19:28,100 it's not going to be able to stick 302 00:19:28,100 --> 00:19:32,610 to this MHC-peptide complex. 303 00:19:32,610 --> 00:19:35,420 However, if I had a T cell receptor that 304 00:19:35,420 --> 00:19:37,270 had the right conformation, because there 305 00:19:37,270 --> 00:19:39,560 are different types of T cell receptors, 306 00:19:39,560 --> 00:19:42,650 it might be able to dock on and stick to the peptide, 307 00:19:42,650 --> 00:19:49,880 and then the T cell is now stuck to the peptide-MHC complex, OK? 308 00:19:49,880 --> 00:19:52,040 So there are different T cell receptors. 309 00:19:52,040 --> 00:19:54,470 There's a diversity of T cell receptors, 310 00:19:54,470 --> 00:19:58,280 and they're able to discriminate between different peptides 311 00:19:58,280 --> 00:19:59,255 loaded onto MHC. 312 00:20:07,530 --> 00:20:10,680 OK, so now, we have to think about where this diversity of T 313 00:20:10,680 --> 00:20:12,180 cell receptors comes from. 314 00:20:15,600 --> 00:20:20,130 There's a diversity of TCRs, and lucky for you, 315 00:20:20,130 --> 00:20:23,610 the mechanism that generates the diversity of TCRs 316 00:20:23,610 --> 00:20:28,470 is the same that generates diversity for antibodies. 317 00:20:28,470 --> 00:20:31,320 Now, Georgia asked a really good and really important 318 00:20:31,320 --> 00:20:34,750 question at the end of lecture on Wednesday, 319 00:20:34,750 --> 00:20:38,820 which is-- she asked if this sort of rearrangement 320 00:20:38,820 --> 00:20:44,430 of gene segments in the variable domain of the antibody 321 00:20:44,430 --> 00:20:49,340 was due to splicing or recombination 322 00:20:49,340 --> 00:20:51,480 at the genomic locus. 323 00:20:51,480 --> 00:20:53,610 And the answer is that it's recombination 324 00:20:53,610 --> 00:20:58,270 at the genomic locus, and that's a very important point. 325 00:20:58,270 --> 00:21:01,920 So here's a diagram for the beta chain of the TCR. 326 00:21:01,920 --> 00:21:05,290 You can see that like the B cell receptor, 327 00:21:05,290 --> 00:21:08,820 there's a gene rearrangement in the genomic DNA that 328 00:21:08,820 --> 00:21:11,490 brings V, D, and J segments together to make 329 00:21:11,490 --> 00:21:15,510 the variable chain of the T cell receptor. 330 00:21:15,510 --> 00:21:24,930 So like the B cell receptor, there is a gene rearrangement, 331 00:21:24,930 --> 00:21:33,330 also known as VDJ recombination, and this is not 332 00:21:33,330 --> 00:21:35,310 splicing of the transcript. 333 00:21:35,310 --> 00:21:37,110 This is in the genomic DNA-- 334 00:21:37,110 --> 00:21:40,890 a very important point, because by having 335 00:21:40,890 --> 00:21:44,250 this happen in the genomic DNA, it 336 00:21:44,250 --> 00:21:48,810 creates an irreversible change in that genomic DNA 337 00:21:48,810 --> 00:21:51,330 such that all subsequent cells that 338 00:21:51,330 --> 00:21:55,050 are derived from that original B or T cell 339 00:21:55,050 --> 00:22:00,480 are going to express the identical B or T cell receptor. 340 00:22:00,480 --> 00:22:02,850 So it's not splicing, but it's a real sort 341 00:22:02,850 --> 00:22:06,150 of irreversible change to the genomic DNA. 342 00:22:10,290 --> 00:22:14,070 So you have a diversity of T cell receptors, but the T cell 343 00:22:14,070 --> 00:22:17,100 receptor is not the only thing that 344 00:22:17,100 --> 00:22:22,500 enables the T cell to interact with whatever cell 345 00:22:22,500 --> 00:22:27,060 is presenting the antigen. There are these other co-receptors 346 00:22:27,060 --> 00:22:30,070 which are important. 347 00:22:30,070 --> 00:22:34,680 So there are co-receptors on the T cell-- 348 00:22:34,680 --> 00:22:36,000 this is on the T cell-- 349 00:22:38,730 --> 00:22:44,250 and the co-receptors are CD4 and CD8, 350 00:22:44,250 --> 00:22:46,845 and they're expressed on different subsets of T cells. 351 00:22:51,540 --> 00:22:54,960 And these co-receptors-- because it's not sufficient 352 00:22:54,960 --> 00:22:59,370 for just the T cell receptor to interact 353 00:22:59,370 --> 00:23:02,490 with a specific peptide, it also requires 354 00:23:02,490 --> 00:23:06,630 this co-receptor in order to get an immune response. 355 00:23:06,630 --> 00:23:08,640 So the logic is that if the T cell 356 00:23:08,640 --> 00:23:15,660 receptor and the co-receptor both bind to the MHC, 357 00:23:15,660 --> 00:23:20,340 then you get a particular type of response, so you need both. 358 00:23:20,340 --> 00:23:27,810 And CD4 cells recognize the class 2 of MHC. 359 00:23:32,330 --> 00:23:37,475 CD8 recognizes class 1 MHC. 360 00:23:46,950 --> 00:23:50,880 So you have these two different subsets of T cells 361 00:23:50,880 --> 00:23:56,850 and they recognize these distinct MHC complexes. 362 00:23:56,850 --> 00:24:00,600 So my question for you is what should these CD8 positive T 363 00:24:00,600 --> 00:24:01,410 cells do? 364 00:24:04,295 --> 00:24:05,670 To help with that, you might want 365 00:24:05,670 --> 00:24:09,840 to look at where the peptides are coming from that 366 00:24:09,840 --> 00:24:14,610 are presented on the class 1 MHCs, which are going to be 367 00:24:14,610 --> 00:24:18,600 presenting specifically to CD8. 368 00:24:18,600 --> 00:24:19,650 So what should these do? 369 00:24:24,630 --> 00:24:31,670 What does it mean if you have a class 1 MHC molecule containing 370 00:24:31,670 --> 00:24:32,890 a peptide that looks foreign? 371 00:24:35,930 --> 00:24:39,470 Well, where do the peptides come from? 372 00:24:39,470 --> 00:24:42,000 What's that, Patricia? 373 00:24:42,000 --> 00:24:42,940 Patricia is right. 374 00:24:42,940 --> 00:24:44,700 They're coming from the cytosol. 375 00:24:44,700 --> 00:24:48,120 So if you have foreign elements coming from the cytosol, 376 00:24:48,120 --> 00:24:49,940 what might that mean for that cell? 377 00:24:52,560 --> 00:24:57,250 Good, bad, irrelevant? 378 00:24:57,250 --> 00:24:58,090 What's that? 379 00:24:58,090 --> 00:25:00,340 AUDIENCE: [INAUDIBLE] 380 00:25:01,112 --> 00:25:02,070 PROFESSOR: What's that? 381 00:25:02,070 --> 00:25:04,210 OK, Brett's saying it needs to be dealt with, 382 00:25:04,210 --> 00:25:05,690 and I totally agree. 383 00:25:05,690 --> 00:25:07,920 Here's one scenario-- would be the scenario 384 00:25:07,920 --> 00:25:09,960 I showed you in the beginning of class 385 00:25:09,960 --> 00:25:13,110 where you have some sort of intracellular parasite 386 00:25:13,110 --> 00:25:17,460 that is basically using the host cell for its own evil purposes 387 00:25:17,460 --> 00:25:22,350 to produce more viruses or more bacteria. 388 00:25:22,350 --> 00:25:27,780 So if the immune cell has some sort of indication 389 00:25:27,780 --> 00:25:31,760 that this is going wrong, another example is in cancer, 390 00:25:31,760 --> 00:25:36,450 because if you have oncogenic mutations in certain genes, 391 00:25:36,450 --> 00:25:39,520 then those could be recognized as foreign. 392 00:25:39,520 --> 00:25:42,540 And so an appropriate response might 393 00:25:42,540 --> 00:25:45,300 be to do something to that cell that would limit 394 00:25:45,300 --> 00:25:47,820 the expansion of the tumor. 395 00:25:47,820 --> 00:25:50,880 Or in the case of an intracellular parasite, 396 00:25:50,880 --> 00:25:54,030 you really need to terminate the cell 397 00:25:54,030 --> 00:25:57,360 so that you stem the tide of viruses that are going 398 00:25:57,360 --> 00:26:00,210 to be produced by that cell. 399 00:26:00,210 --> 00:26:03,410 So the response should be to kill. 400 00:26:03,410 --> 00:26:04,950 So it was CD8 positive. 401 00:26:10,260 --> 00:26:13,755 If you have a CD8 positive T cell, 402 00:26:13,755 --> 00:26:17,400 it indicates there's something wrong inside that cell, 403 00:26:17,400 --> 00:26:21,750 and the response should be to kill it. 404 00:26:21,750 --> 00:26:25,020 And these CD8 positive T cells are known 405 00:26:25,020 --> 00:26:33,175 as killer or cytotoxic T cells. 406 00:26:37,610 --> 00:26:42,080 So what happens if a CD8 positive T cell recognizes 407 00:26:42,080 --> 00:26:47,270 a MHC class 1 peptide complex, then it 408 00:26:47,270 --> 00:26:52,070 releases materials from inside it that perforate that cell 409 00:26:52,070 --> 00:26:55,040 and lead it to undergo cell death. 410 00:26:55,040 --> 00:26:57,050 So it's a way of limiting an infection 411 00:26:57,050 --> 00:27:01,430 by killing the cells that the virus or pathogen is 412 00:27:01,430 --> 00:27:04,540 using to reproduce itself. 413 00:27:04,540 --> 00:27:09,230 OK, what about CD4 positive? 414 00:27:09,230 --> 00:27:12,390 What should be the response of a CD4 positive T cell? 415 00:27:18,220 --> 00:27:19,630 Should it also kill? 416 00:27:19,630 --> 00:27:24,240 Should be like the T-1000? 417 00:27:24,240 --> 00:27:26,160 No one gets my cultural references. 418 00:27:26,160 --> 00:27:27,880 Yeah. 419 00:27:27,880 --> 00:27:30,100 Should it be the Terminator 2? 420 00:27:30,100 --> 00:27:31,330 No. 421 00:27:31,330 --> 00:27:31,830 Yes or no? 422 00:27:31,830 --> 00:27:33,180 Who thinks it should terminate? 423 00:27:36,560 --> 00:27:37,850 OK. 424 00:27:37,850 --> 00:27:39,885 Steven, can you tell us your logic? 425 00:27:42,490 --> 00:27:43,690 Why should it not terminate? 426 00:27:43,690 --> 00:27:46,400 AUDIENCE: Because it's a [INAUDIBLE] B 427 00:27:46,400 --> 00:27:50,460 cell from the same [INAUDIBLE]. 428 00:27:50,460 --> 00:27:54,030 PROFESSOR: What are the MHC class 2 cells? 429 00:27:54,030 --> 00:27:56,693 AUDIENCE: Like, a B cell or [INAUDIBLE].. 430 00:27:56,693 --> 00:27:57,360 PROFESSOR: Yeah. 431 00:27:57,360 --> 00:27:58,902 It's not only a B cell, it's a B cell 432 00:27:58,902 --> 00:28:01,477 that recognizes the foreign agent 433 00:28:01,477 --> 00:28:02,560 that you're infected with. 434 00:28:02,560 --> 00:28:04,185 Yeah, Brett? 435 00:28:04,185 --> 00:28:08,280 AUDIENCE: So those B cells are antigen presenting cells. 436 00:28:08,280 --> 00:28:10,528 They have the information about what is bad 437 00:28:10,528 --> 00:28:13,200 or what is wrong in probably other cells? 438 00:28:13,200 --> 00:28:15,250 So like, oh, hey, we have this information. 439 00:28:15,250 --> 00:28:17,700 You should go and mobilize. 440 00:28:17,700 --> 00:28:19,200 PROFESSOR: They're binding something 441 00:28:19,200 --> 00:28:22,560 that it recognizes as foreign, internalizing it, and then 442 00:28:22,560 --> 00:28:25,500 presenting bits of that foreign element 443 00:28:25,500 --> 00:28:26,610 on the outside of itself. 444 00:28:26,610 --> 00:28:27,440 AUDIENCE: Shoots the messenger. 445 00:28:27,440 --> 00:28:27,870 PROFESSOR: What's that? 446 00:28:27,870 --> 00:28:29,610 It's shooting the messenger, exactly. 447 00:28:29,610 --> 00:28:30,630 Yeah. 448 00:28:30,630 --> 00:28:36,580 So it would be an extremely bad idea for the CD4 positive T 449 00:28:36,580 --> 00:28:39,930 cell to kill what's presenting the antigen, 450 00:28:39,930 --> 00:28:44,100 because you would kill the exact cell that you would need 451 00:28:44,100 --> 00:28:45,960 to fight that antigen, right? 452 00:28:45,960 --> 00:28:47,500 Here you have a B cell. 453 00:28:47,500 --> 00:28:50,730 It would be a B cell that's producing an antibody that 454 00:28:50,730 --> 00:28:52,980 actually can produce antibodies that 455 00:28:52,980 --> 00:28:56,790 might be able to neutralize that foreign invader, 456 00:28:56,790 --> 00:28:58,950 and so you don't want to kill it. 457 00:28:58,950 --> 00:29:03,880 You want to help it or enhance the B cell function. 458 00:29:08,660 --> 00:29:19,260 And so these CD4 positive cells are known as helper T cells, 459 00:29:19,260 --> 00:29:24,000 and they enhance B cell function in a number of different ways. 460 00:29:24,000 --> 00:29:27,000 Oh, I should point out where this happens. 461 00:29:27,000 --> 00:29:30,630 So this sort of interaction between B and T cells 462 00:29:30,630 --> 00:29:34,740 happens in the lymph node, because in the lymph node, 463 00:29:34,740 --> 00:29:38,280 you have antigen-presenting cells, or even 464 00:29:38,280 --> 00:29:41,970 soluble antigens, coming into these lymph nodes. 465 00:29:41,970 --> 00:29:44,400 And you also have B and T cells, and this 466 00:29:44,400 --> 00:29:47,670 is kind of like the B and T cell hangout 467 00:29:47,670 --> 00:29:50,820 to get sort of, like, interactions between these two 468 00:29:50,820 --> 00:29:52,920 distinct immune cell types. 469 00:29:55,470 --> 00:29:58,920 And when you get sort of a B cell 470 00:29:58,920 --> 00:30:02,580 that presents an antigen that's recognized by a T cell, 471 00:30:02,580 --> 00:30:05,760 then the T cell enhances B cell function, 472 00:30:05,760 --> 00:30:09,040 and it does so in a number of different ways. 473 00:30:09,040 --> 00:30:13,440 The first way that it induces a response in the B cell, 474 00:30:13,440 --> 00:30:15,480 known as affinity maturation. 475 00:30:21,740 --> 00:30:26,340 And this affinity maturation results from a hypermutation 476 00:30:26,340 --> 00:30:29,250 of the variable domain of the antibody such 477 00:30:29,250 --> 00:30:31,950 that you get even more diversity, and such 478 00:30:31,950 --> 00:30:36,390 that a B cell can be selected that even has a tighter binding 479 00:30:36,390 --> 00:30:38,670 to the antigen. 480 00:30:38,670 --> 00:30:41,550 So for affinity maturation, this is 481 00:30:41,550 --> 00:30:46,500 responsible for the transition in binding 482 00:30:46,500 --> 00:30:50,980 from a more weak binding to a tighter binding, 483 00:30:50,980 --> 00:30:52,950 which I talked about as being a difference 484 00:30:52,950 --> 00:30:56,610 between the primary infection and the secondary sort 485 00:30:56,610 --> 00:30:58,710 of immune response, OK? 486 00:30:58,710 --> 00:31:02,250 So the antibodies get better because of this B and T cell 487 00:31:02,250 --> 00:31:05,130 interaction and this affinity maturation process. 488 00:31:08,230 --> 00:31:13,410 One other thing that happens is that the B cells can produce 489 00:31:13,410 --> 00:31:17,580 different classes or isotypes of antibodies, 490 00:31:17,580 --> 00:31:20,162 and this is known as isotype switching. 491 00:31:29,330 --> 00:31:32,150 And so this is, again, the genomic locus 492 00:31:32,150 --> 00:31:37,430 for the heavy chain of an immunoglobulin. 493 00:31:37,430 --> 00:31:39,740 You see, here's the VDJ segment, so it's 494 00:31:39,740 --> 00:31:43,400 undergone VDJ recombination, and then 495 00:31:43,400 --> 00:31:47,000 what you see are these different blue regions here. 496 00:31:47,000 --> 00:31:51,380 Each of these are exons that encode a different isotope 497 00:31:51,380 --> 00:31:53,840 for the antibody. 498 00:31:53,840 --> 00:31:56,000 So the first one is mu, and so that 499 00:31:56,000 --> 00:32:02,300 produces IgM when that's the one that's proximal to VDJ. 500 00:32:02,300 --> 00:32:08,560 So if you have IgM, that's the initial state of the antibody, 501 00:32:08,560 --> 00:32:10,820 and that's initially membrane bound 502 00:32:10,820 --> 00:32:14,350 and serves as the B cell receptor. 503 00:32:14,350 --> 00:32:18,320 But each of these different constant domains, 504 00:32:18,320 --> 00:32:20,870 even though they're not undergoing variation, 505 00:32:20,870 --> 00:32:23,030 they have different effector functions 506 00:32:23,030 --> 00:32:26,420 and can do different things for the body. 507 00:32:26,420 --> 00:32:31,100 So for example, if you had isotype switching 508 00:32:31,100 --> 00:32:33,140 and you had a recombination event that 509 00:32:33,140 --> 00:32:37,160 brought this gamma 2 segment together with VDJ, 510 00:32:37,160 --> 00:32:41,940 that would produce the isotype which is known as IgG, 511 00:32:41,940 --> 00:32:47,060 and IgG is a highly secreted form of the antibody that 512 00:32:47,060 --> 00:32:50,930 is highly effective for bacterial infections 513 00:32:50,930 --> 00:32:53,180 because it's secreted in the blood, 514 00:32:53,180 --> 00:32:56,720 and it's able to neutralize bacteria and limit 515 00:32:56,720 --> 00:32:59,570 the infection that way. 516 00:32:59,570 --> 00:33:01,430 But there are other possibilities, 517 00:33:01,430 --> 00:33:04,610 because you have all of these different possibilities. 518 00:33:04,610 --> 00:33:08,630 And so you could get VDJ together with this alpha, 519 00:33:08,630 --> 00:33:13,300 and that would produce an isotype known as IgA. 520 00:33:13,300 --> 00:33:16,430 And IgA promotes mucosal immunity 521 00:33:16,430 --> 00:33:18,980 because it's able to pass through the epithelial linings. 522 00:33:21,890 --> 00:33:26,130 In addition, IgE is another type of antibody, 523 00:33:26,130 --> 00:33:29,900 and the constant domains are constant for each of isotypes, 524 00:33:29,900 --> 00:33:33,860 but they recruit different effector functions. 525 00:33:33,860 --> 00:33:41,630 So IgG would be hitting bacteria by promoting 526 00:33:41,630 --> 00:33:46,370 phagocytosis of those bacteria. 527 00:33:46,370 --> 00:33:51,150 IgE, in contrast, is especially good at dealing with worms, 528 00:33:51,150 --> 00:33:51,650 right? 529 00:33:51,650 --> 00:33:53,810 So if you have an intracellular-- 530 00:33:53,810 --> 00:33:57,530 or not intracellular, but like, an intestinal worm or something 531 00:33:57,530 --> 00:34:01,060 like that, then IgE-- 532 00:34:01,060 --> 00:34:04,970 its effector functions are better at dealing with that. 533 00:34:04,970 --> 00:34:08,120 So this process of isotype switching sort of 534 00:34:08,120 --> 00:34:12,139 allows the immune system to adapt to tackle 535 00:34:12,139 --> 00:34:16,980 a particular type of pathogen. 536 00:34:16,980 --> 00:34:17,480 All right. 537 00:34:17,480 --> 00:34:24,050 The last way in which T cells enhance this function 538 00:34:24,050 --> 00:34:28,070 is by promoting the differentiation of B cells 539 00:34:28,070 --> 00:34:30,139 into different types of B cells. 540 00:34:30,139 --> 00:34:34,480 One of those types of B cells is known as a memory B cell, 541 00:34:34,480 --> 00:34:37,190 and the memory B cell is a B cell 542 00:34:37,190 --> 00:34:39,710 that can last in the body for decades, 543 00:34:39,710 --> 00:34:44,000 even if the antigen is not present. 544 00:34:44,000 --> 00:34:49,250 So this mediates sort of the memory of the immune system. 545 00:34:49,250 --> 00:34:55,310 And so just to summarize what I just told you, 546 00:34:55,310 --> 00:34:59,000 if you have a B cell and it recognizes an antigen, which 547 00:34:59,000 --> 00:35:02,960 could be a protein, it would internalize that protein 548 00:35:02,960 --> 00:35:06,020 via endocytosis and then process it 549 00:35:06,020 --> 00:35:09,710 so that it can display peptides from that antigen 550 00:35:09,710 --> 00:35:11,240 on its surface. 551 00:35:11,240 --> 00:35:15,230 And if that's recognized by a T cell, 552 00:35:15,230 --> 00:35:18,440 then that leads to an interaction between the T and B 553 00:35:18,440 --> 00:35:22,080 cell that will lead to these different things happening, 554 00:35:22,080 --> 00:35:26,120 such as affinity maturation, isotype switching, 555 00:35:26,120 --> 00:35:29,060 so the red here would be a different constant chain 556 00:35:29,060 --> 00:35:31,860 on this same variable chain. 557 00:35:31,860 --> 00:35:34,340 So the variable chain doesn't change 558 00:35:34,340 --> 00:35:36,590 with the isotype switching, so it's still always 559 00:35:36,590 --> 00:35:38,530 able to recognize that antigen-- 560 00:35:38,530 --> 00:35:40,910 it's just recruiting different effector functions. 561 00:35:43,650 --> 00:35:46,190 And you can also get differentiation of B cells 562 00:35:46,190 --> 00:35:50,330 into plasma cells, which really secrete a ton of antibody, 563 00:35:50,330 --> 00:35:54,110 and therefore help the body fight infection. 564 00:35:54,110 --> 00:35:59,910 Now this is important because for a vaccine to be effective, 565 00:35:59,910 --> 00:36:03,530 you need to engage this T cell response such 566 00:36:03,530 --> 00:36:06,960 that you have all of these things happening. 567 00:36:06,960 --> 00:36:09,380 So all of these things need to happen 568 00:36:09,380 --> 00:36:11,960 for an effective vaccine. 569 00:36:16,610 --> 00:36:18,860 So for an effective vaccine, you can't just 570 00:36:18,860 --> 00:36:21,980 activate the humoral side of the immune system. 571 00:36:21,980 --> 00:36:24,230 You have to activate both the humoral 572 00:36:24,230 --> 00:36:27,920 and the cell-mediated sides such that they interact in order 573 00:36:27,920 --> 00:36:30,965 to enhance the immune response. 574 00:36:34,710 --> 00:36:35,210 All right. 575 00:36:35,210 --> 00:36:38,740 Now I'm going to move on and talk about a big problem 576 00:36:38,740 --> 00:36:41,230 that the immune system has, which 577 00:36:41,230 --> 00:36:44,410 is that it needs to somehow be able to discriminate 578 00:36:44,410 --> 00:36:48,700 between self and foreign, right? 579 00:36:48,700 --> 00:36:52,690 And so if you have your immune system recognizing 580 00:36:52,690 --> 00:36:56,170 an antigen that is natively part of your body, 581 00:36:56,170 --> 00:36:59,050 that results in an autoimmune disease. 582 00:36:59,050 --> 00:37:01,990 So there's a balance in the immune system 583 00:37:01,990 --> 00:37:07,930 between tolerating antigens or attacking them, 584 00:37:07,930 --> 00:37:11,860 and if it's attacking a native antigen, then it's autoimmune. 585 00:37:16,880 --> 00:37:18,380 And this is a huge problem because, 586 00:37:18,380 --> 00:37:21,920 if you think about it, because we've talked about the B cell 587 00:37:21,920 --> 00:37:25,100 receptor, the antibody, and the T cell receptor, right? 588 00:37:25,100 --> 00:37:28,010 Our bodies are generating tens of millions 589 00:37:28,010 --> 00:37:30,800 of these receptors that are diverse and can 590 00:37:30,800 --> 00:37:33,410 recognize different molecules. 591 00:37:33,410 --> 00:37:38,540 So our body is generating tens of millions 592 00:37:38,540 --> 00:37:46,770 of antigen receptors, and it does this constitutively, 593 00:37:46,770 --> 00:37:49,890 so that means that it's just doing it automatically. 594 00:37:49,890 --> 00:37:52,230 You don't even need to be infected for this to happen. 595 00:37:52,230 --> 00:37:56,730 This is just part of the development of B and T cells. 596 00:37:56,730 --> 00:38:00,860 OK, so it's constitutive, doesn't require infection-- 597 00:38:00,860 --> 00:38:01,710 constitutive. 598 00:38:04,400 --> 00:38:07,700 In addition, it's totally random. 599 00:38:07,700 --> 00:38:12,080 Your body could generate any sort of combination of V, Ds, 600 00:38:12,080 --> 00:38:15,200 and Js, and it could mutate in a certain way 601 00:38:15,200 --> 00:38:18,440 that it's likely that at some point during your lifetime 602 00:38:18,440 --> 00:38:20,930 you're going to generate a receptor that recognizes 603 00:38:20,930 --> 00:38:23,020 a native protein in your body. 604 00:38:23,020 --> 00:38:24,020 So it's totally random-- 605 00:38:26,930 --> 00:38:33,140 at least what the sort of rearrangement of VDJ gives. 606 00:38:33,140 --> 00:38:37,340 That process is constitutive and random. 607 00:38:37,340 --> 00:38:39,880 So I just want to point out several diseases that 608 00:38:39,880 --> 00:38:44,570 are caused by autoimmunity, and I've distinguished them 609 00:38:44,570 --> 00:38:47,810 based on whether the disease involves 610 00:38:47,810 --> 00:38:51,230 the generation of antibodies that recognize self or T 611 00:38:51,230 --> 00:38:53,840 cells that recognize self. 612 00:38:53,840 --> 00:38:58,370 So for antibodies, there's a disease, myasthenia gravis, 613 00:38:58,370 --> 00:39:01,640 which an individual's-- individuals generate 614 00:39:01,640 --> 00:39:05,930 an antibody against a receptor for a neurotransmitter, 615 00:39:05,930 --> 00:39:07,940 acetylcholine. 616 00:39:07,940 --> 00:39:10,670 And acetylcholine is the neurotransmitter 617 00:39:10,670 --> 00:39:14,570 which is predominantly involved in sending signals from a motor 618 00:39:14,570 --> 00:39:17,180 neuron to a muscle, and therefore 619 00:39:17,180 --> 00:39:19,820 antibodies that inhibit this receptor 620 00:39:19,820 --> 00:39:23,450 result in muscle weakness. 621 00:39:23,450 --> 00:39:27,140 Now self antibodies can also result in diabetes, 622 00:39:27,140 --> 00:39:29,270 and individuals can develop antibodies 623 00:39:29,270 --> 00:39:32,480 that recognize and inhibit the insulin receptor, 624 00:39:32,480 --> 00:39:36,440 and this leads to insulin resistance and diabetes 625 00:39:36,440 --> 00:39:39,020 mellitus. 626 00:39:39,020 --> 00:39:42,500 Some examples of T cell mediated diseases 627 00:39:42,500 --> 00:39:45,020 are-- if you recall back in the beginning of the month, 628 00:39:45,020 --> 00:39:48,320 when we talked about electrical signaling in neurons, 629 00:39:48,320 --> 00:39:50,870 I told you about the myelin sheath 630 00:39:50,870 --> 00:39:54,950 and how this increases the speed of the action 631 00:39:54,950 --> 00:39:58,370 potential along that axon. 632 00:39:58,370 --> 00:40:02,510 And if T cells attack the myelin sheath, 633 00:40:02,510 --> 00:40:06,820 then it disrupts this process of electrical signaling, 634 00:40:06,820 --> 00:40:09,170 and that results in a devastating disease, 635 00:40:09,170 --> 00:40:11,570 which is multiple sclerosis. 636 00:40:11,570 --> 00:40:16,680 Autoimmune disease involving T cells also involves diabetes, 637 00:40:16,680 --> 00:40:18,950 and if T cells attack and destroy 638 00:40:18,950 --> 00:40:23,720 the islet cells of the pancreas, this also 639 00:40:23,720 --> 00:40:26,780 disrupts the body's ability to produce insulin, 640 00:40:26,780 --> 00:40:30,260 and that results in type 1 diabetes. 641 00:40:30,260 --> 00:40:33,470 So I'm sure many of you know people 642 00:40:33,470 --> 00:40:37,970 with these types of diseases, and they're obviously 643 00:40:37,970 --> 00:40:41,600 of significant impact both in this country 644 00:40:41,600 --> 00:40:42,650 and around the world. 645 00:40:45,350 --> 00:40:49,520 So the problem for the cells in our body and the immune system 646 00:40:49,520 --> 00:40:54,050 is that the immune system has to have some sort of way 647 00:40:54,050 --> 00:40:57,590 to distinguish between self and foreign. 648 00:41:00,660 --> 00:41:04,760 So how is it that the immune system does this? 649 00:41:04,760 --> 00:41:07,490 And also, it has to have different responses 650 00:41:07,490 --> 00:41:10,760 to self-recognition versus foreign recognition. 651 00:41:13,820 --> 00:41:15,830 So what should the immune system's response 652 00:41:15,830 --> 00:41:20,950 be if there is a self recognition? 653 00:41:20,950 --> 00:41:22,600 What should it do to the cells that 654 00:41:22,600 --> 00:41:24,270 recognizes a native protein? 655 00:41:24,270 --> 00:41:25,173 Rachel? 656 00:41:25,173 --> 00:41:27,640 AUDIENCE: [INAUDIBLE] 657 00:41:27,640 --> 00:41:29,380 PROFESSOR: It could delete that cell. 658 00:41:29,380 --> 00:41:32,020 What Rachel said is you should get rid of it. 659 00:41:32,020 --> 00:41:36,220 And so one way to think about this process 660 00:41:36,220 --> 00:41:40,210 is there's a bit of a Darwinian natural selection going on 661 00:41:40,210 --> 00:41:43,960 in the body, and if there is a self recognition, 662 00:41:43,960 --> 00:41:48,370 then there should be a negative selection against that cell, 663 00:41:48,370 --> 00:41:50,410 so there should be negative selection. 664 00:41:50,410 --> 00:41:55,600 This cell should be more unfit, whereas if it's 665 00:41:55,600 --> 00:41:59,160 obviously foreign, then there should be positive selection. 666 00:41:59,160 --> 00:42:00,910 This B cell should be more fit. 667 00:42:05,170 --> 00:42:07,690 And what Rachel suggested is to get rid 668 00:42:07,690 --> 00:42:10,480 of the cell, which is a great idea, because if you kill off 669 00:42:10,480 --> 00:42:13,750 the cell then you won't generate any more cells that have 670 00:42:13,750 --> 00:42:16,210 that recognition against self. 671 00:42:16,210 --> 00:42:21,110 So negative selection is mediated by apoptosis and cell 672 00:42:21,110 --> 00:42:21,610 death. 673 00:42:26,710 --> 00:42:30,760 And positive selection could be both the activation of the cell 674 00:42:30,760 --> 00:42:32,740 and also its proliferation. 675 00:42:32,740 --> 00:42:36,240 As you see up on the slide there, that orange cell-- 676 00:42:36,240 --> 00:42:40,260 if it was recognizing a foreign antigen, would get activated 677 00:42:40,260 --> 00:42:43,720 and it would undergo a monoclonal expansion. 678 00:42:43,720 --> 00:42:46,450 All the cells resulting from that expansion 679 00:42:46,450 --> 00:42:49,420 would express the same antibody and therefore recognize 680 00:42:49,420 --> 00:42:52,750 that antigen, so this would result 681 00:42:52,750 --> 00:42:59,650 in cell division or expansion of that population of cell. 682 00:43:06,420 --> 00:43:12,380 So now we know what to do with self versus foreign, 683 00:43:12,380 --> 00:43:14,420 but how is it that we distinguish 684 00:43:14,420 --> 00:43:16,640 between self and foreign? 685 00:43:16,640 --> 00:43:29,480 So how does the immune system distinguish self from foreign? 686 00:43:29,480 --> 00:43:33,570 And there are several mechanisms to do this. 687 00:43:33,570 --> 00:43:37,820 The first is that the organs-- 688 00:43:37,820 --> 00:43:40,850 the lymphoid organs-- where are these B and T cells 689 00:43:40,850 --> 00:43:44,720 mature and undergo these genomic rearrangements 690 00:43:44,720 --> 00:43:47,315 are largely protected from foreign agents. 691 00:43:49,910 --> 00:43:58,760 So there are basically only self antigens 692 00:43:58,760 --> 00:44:02,645 in the generative lymphoid organs. 693 00:44:06,770 --> 00:44:09,050 These are the lymphoid organs were B and T 694 00:44:09,050 --> 00:44:10,340 cells are being generated. 695 00:44:13,340 --> 00:44:15,440 So the generative lymphoid organs 696 00:44:15,440 --> 00:44:21,830 would be the bone marrow for B cells 697 00:44:21,830 --> 00:44:23,330 and the thymus for T cells. 698 00:44:26,090 --> 00:44:29,150 Therefore, if a B or T cell-- 699 00:44:29,150 --> 00:44:31,430 if its receptor engages with something 700 00:44:31,430 --> 00:44:33,950 very tightly during its development, 701 00:44:33,950 --> 00:44:36,950 that's a signal for the immune system 702 00:44:36,950 --> 00:44:39,020 to delete and kill off that cell. 703 00:44:43,430 --> 00:44:46,100 So if you get self recognition here, 704 00:44:46,100 --> 00:44:50,310 you get apoptosis and deletion of that cell. 705 00:44:50,310 --> 00:44:54,470 The second way that the body is able to distinguish 706 00:44:54,470 --> 00:45:01,160 is that it responds to antigens specifically 707 00:45:01,160 --> 00:45:04,022 when there is an innate immune response, 708 00:45:04,022 --> 00:45:05,480 or if it responds better when there 709 00:45:05,480 --> 00:45:07,075 is an innate immune response. 710 00:45:13,410 --> 00:45:17,540 So you can think of it like a coincidence detector, right? 711 00:45:17,540 --> 00:45:21,380 If you have an immune cell and it recognizes an antigen, 712 00:45:21,380 --> 00:45:24,080 and there's also an innate immune response, 713 00:45:24,080 --> 00:45:28,880 that's a strong indication that this is foreign. 714 00:45:28,880 --> 00:45:31,700 So this would indicate "foreign" to the immune system. 715 00:45:35,350 --> 00:45:40,010 If there is antigen only and the body is not 716 00:45:40,010 --> 00:45:42,830 mounting an innate immune response, 717 00:45:42,830 --> 00:45:46,760 it's much more likely that this will generate 718 00:45:46,760 --> 00:45:51,020 a robust immune response, and this is the immune system's 719 00:45:51,020 --> 00:45:57,260 signal that this is a self antigen. 720 00:45:57,260 --> 00:46:00,530 This is also important for vaccine development 721 00:46:00,530 --> 00:46:02,600 because in most vaccines, in addition 722 00:46:02,600 --> 00:46:07,990 to having some antigen that's a part of the infectious agent, 723 00:46:07,990 --> 00:46:14,060 there's also something called an adjuvant, which is basically 724 00:46:14,060 --> 00:46:18,500 something that activates the innate immune system. 725 00:46:18,500 --> 00:46:22,940 So the adjuvant activates the innate immune response, 726 00:46:22,940 --> 00:46:25,700 and that's important because if you just 727 00:46:25,700 --> 00:46:27,890 had the vaccine with just the antigen, 728 00:46:27,890 --> 00:46:31,550 there wouldn't be nearly as robust a response. 729 00:46:31,550 --> 00:46:37,490 So you need both to activate the adaptive immune system, 730 00:46:37,490 --> 00:46:40,460 but also the innate immune system to really get 731 00:46:40,460 --> 00:46:41,810 a robust response. 732 00:46:46,130 --> 00:46:50,180 So I want to end by talking about this year's Nobel Prize 733 00:46:50,180 --> 00:46:56,330 work, and it involves another mechanism that 734 00:46:56,330 --> 00:46:59,960 basically prevents autoimmunity and downregulates 735 00:46:59,960 --> 00:47:06,890 the activity of these T cells, and that 736 00:47:06,890 --> 00:47:09,920 involves another type of-- we've only talked about activating 737 00:47:09,920 --> 00:47:11,300 receptors on the T cell, right? 738 00:47:11,300 --> 00:47:14,450 The T cell receptor, CD4, CD8-- 739 00:47:14,450 --> 00:47:17,820 they're activating receptors for the T cell receptor, 740 00:47:17,820 --> 00:47:21,500 but there are also inhibitory receptors that 741 00:47:21,500 --> 00:47:24,000 are on the surface of T cells. 742 00:47:24,000 --> 00:47:27,830 So inhibitory-- we'll just call them receptors. 743 00:47:27,830 --> 00:47:33,260 One is called CTLA4 and another is called PD1. 744 00:47:37,790 --> 00:47:41,180 Their names are not terribly important, but what they do 745 00:47:41,180 --> 00:47:44,870 is they keep the immune system in check. 746 00:47:44,870 --> 00:47:46,670 And we've talked a lot about signaling 747 00:47:46,670 --> 00:47:49,310 and how signaling gets activated, 748 00:47:49,310 --> 00:47:53,600 and often a step in signaling is once you get the signal sent, 749 00:47:53,600 --> 00:47:57,080 and it's been sent, there is, like, a negative feedback 750 00:47:57,080 --> 00:47:59,390 that then turns off the signal such 751 00:47:59,390 --> 00:48:02,030 that there's signal termination. 752 00:48:02,030 --> 00:48:04,850 So you often have some type of signal termination. 753 00:48:08,000 --> 00:48:11,150 That way, you don't have just a constitutive activation 754 00:48:11,150 --> 00:48:13,250 of the signal, which in this case 755 00:48:13,250 --> 00:48:16,760 would be sort of inflammation and an immune response, 756 00:48:16,760 --> 00:48:20,300 and one or both of these is involved 757 00:48:20,300 --> 00:48:22,460 in sort of keeping the immune system in check 758 00:48:22,460 --> 00:48:27,740 and stopping it after you get that initial reaction. 759 00:48:27,740 --> 00:48:29,830 Now, the reason this is so important 760 00:48:29,830 --> 00:48:34,280 and why James Allison and Tasuku Honjo won 761 00:48:34,280 --> 00:48:36,590 the Nobel Prize is they had the idea 762 00:48:36,590 --> 00:48:41,750 to use this as a therapy for cancer. 763 00:48:41,750 --> 00:48:45,380 And it turns out that some cancer cells 764 00:48:45,380 --> 00:48:51,620 can express the ligand for these inhibitory receptors 765 00:48:51,620 --> 00:48:54,830 such that they can avoid the immune system from recognizing 766 00:48:54,830 --> 00:48:56,510 the tumor. 767 00:48:56,510 --> 00:49:01,220 So this would be one case where the tumor cell is expressing 768 00:49:01,220 --> 00:49:05,570 the ligand for PD1, and that inhibits the function of this T 769 00:49:05,570 --> 00:49:09,140 cell receptor so that it doesn't kill the tumor cell, 770 00:49:09,140 --> 00:49:13,080 and that leads to the expansion of the tumor 771 00:49:13,080 --> 00:49:17,300 so the tumor can expand in an unchecked way. 772 00:49:17,300 --> 00:49:22,070 And what James Allison and Tasuku Honjo determined 773 00:49:22,070 --> 00:49:27,050 is that if you block that inhibitory receptor, 774 00:49:27,050 --> 00:49:31,340 then you sort of uncheck the response of the immune system 775 00:49:31,340 --> 00:49:33,260 such that these immune cells are now 776 00:49:33,260 --> 00:49:37,700 able to recognize the tumor cells and kill them. 777 00:49:37,700 --> 00:49:41,780 So by sort of blocking the inhibitor, 778 00:49:41,780 --> 00:49:45,860 you now have T cells-- these are CD8 positive T cells that are 779 00:49:45,860 --> 00:49:47,060 killer cells-- 780 00:49:47,060 --> 00:49:50,120 they will now recognize these T cells and kill them off. 781 00:49:52,940 --> 00:49:58,550 So there's what's known as an inhibitor blockade 782 00:49:58,550 --> 00:50:05,570 because you're blocking the inhibitor, 783 00:50:05,570 --> 00:50:10,340 and these inhibitors are antibodies that recognize 784 00:50:10,340 --> 00:50:14,960 these inhibitory receptors, and they're now being used to treat 785 00:50:14,960 --> 00:50:19,250 some forms of advanced cancer. 786 00:50:19,250 --> 00:50:21,410 And so this is something that the cancer 787 00:50:21,410 --> 00:50:25,580 field and immunology fields are both really excited about. 788 00:50:25,580 --> 00:50:31,130 What might be one complication with this type of treatment? 789 00:50:31,130 --> 00:50:33,290 If you get rid of the inhibitory receptors, 790 00:50:33,290 --> 00:50:35,590 what might be a consequence? 791 00:50:35,590 --> 00:50:36,330 Yeah, Steven? 792 00:50:36,330 --> 00:50:38,665 AUDIENCE: Then you could recognize other self cells that 793 00:50:38,665 --> 00:50:40,070 inhibited [INAUDIBLE]. 794 00:50:40,070 --> 00:50:42,080 PROFESSOR: Yeah, you get autoimmunity. 795 00:50:42,080 --> 00:50:43,250 That's exactly right. 796 00:50:43,250 --> 00:50:46,580 So one of the downsides of this is that-- 797 00:50:46,580 --> 00:50:49,310 one of the side effects is that you can have patients 798 00:50:49,310 --> 00:50:51,690 with an autoimmune reaction. 799 00:50:51,690 --> 00:50:53,900 So it's not the magic bullet, but it's 800 00:50:53,900 --> 00:50:55,880 a step in the right direction. 801 00:50:55,880 --> 00:50:58,840 All right, we'll see you next week.