PROFESSOR: All liberty. So today, we’re going totalk about exemption again. And so this movie upon the screen here– this is a cell. You can see the outline ofthe cells kind of around here. That’s the outline of the cadre. But what you cansee is that there is something in thecell moving around, and that is an intracellularbacteria called listeria. And you can see it’srocketing around in this cell. It’s having a totalparty in this cell, and what you’ll see here is youcan often discover the bacteria push out from the cell. So if you look here, oneis going to push right now. See? There it proceeds. And it various kinds of leads intothe edge of the cell and propagandizes out, and thisenables the bacteria to spread from cell tocell without actually going into the extracellular spacesurrounding the cells, OK? So let’s take ahypothetical situation. So listeria is afoodborne illness. It makes a terrible sortof intestinal infection. So Brett, do you wantthese bacteria having a party in your cadres? AUDIENCE: Unlikely.PROFESSOR: Hell no. OK, Malik, do you wantthese bacteria having a party in your cadres? Hell no. Carmen, do youwant these bacteria having a party in your cells? AUDIENCE: Hell no. PROFESSOR: Hell no! Yes. OK, so our mas has to havesome way to sort of address this type of anillness, and the problem is if you’re thinking about whatwe discussed on Wednesday, is– all right. So you’re hostingthis party, right? This is your cell. So you have a host cell– that’s your cell– and youhave an intracellular pathogen, such as a bacteria or itcould also be a virus, and they’re essentiallyusing your magnanimous multitude cadre to reproduceitself to spread to other cadres of the body.And so you don’t want that, but their own problems is that– I told you about B cells, so remember B cells– they have an antigen receptor. It’s initially ontheir plasma sheath. It are also welcome to secreted, and it’s exuded into the extracellular space. The trouble is that thesepathogens are inside the cell, and there’s a plasmamembrane separating them from the antigen receptors thatyou need to recognize them, OK? So this presents an issue. It’s also the case for Tcells, because as you heard on Wednesday, T cadres onlyhave this membrane-bound form of the receptor, and the antigenrecognition domains of all of these are extracellular, so there is really– with simply this system, there’sno way for your immune cells to see in the cells.So today, I wantto talk about how is it that the immunecells are able– how our immune cadres areable to see within the cell in order to address an infectionlike this one, with listeria. OK? And the first partof the answer is that it involves a processknown as antigen presentation. And antigen presentationis the process by which peptides, so shortsequences of amino battery-acids, are presented and displayedon the surface of the cell for the immune system– for immune cadres to see. So here, peptides aredisplayed on the cell surface for immune cadres to see them. And in this specific case, it’sgoing to be for the T cells to observe what’s goingon inside the cell, OK? So this mechanisminvolves another molecule, which I briefly introduced.It’s called the majorhistocompatibility composite, which is abbreviated MHC. So when I referred to MHCin Wednesday’s lecture, I was referring to this majorhistocompatibility complex. And there are currently twoclasses of MHCs. Thankfully, the firstone is known as class 1, so class 1 MHC, and class1 MHC looks like this. Like many of theimmune receptors that I’ve talked about, it has a heavy series, which is this longpolypeptide light blue, and it has a lightchain in violet. So the MHC is composed of thesetwo separate polypeptides.They’re encoded bydifferent genes, and then it makes intothis structure shown here. So this moleculehas two Ig regions, and these are proximalto the plasma membrane. And this thing is all insertedin the plasma layer. It’s an integralmembrane protein. And then distal tothe plasma tissue is this structurehere, and if you look at the quartz formation, it’s kind of like a sheet– a beta expanse withtwo alpha helices. And wholly what it doesis it basically generates, like, a little cup, OK? So it’s creating, like, a cup.And what sits in this cup is apeptide, so you get peptides, and the peptides sort of sitin that hand, if you will. And some of the amino acids fromthat peptide are sticking out and they’re sort of displayedaway from the MHC molecule. So this is basically a handthat holds peptides and parades them on the outsideof the cadre, right? So the outside ofthe cell here is up. This would be theexoplasm out here, and it’s exposing thesepeptides for immune cadres like T cadres to observe. All claim. So class 1 MHC is aclass that’s expressed on all nucleatedcells in your figure. So that’s all ofyour nucleotide cadres are synthesizingin a class 1 MHC, and then it’s sort of beingdisplayed on the surface.And the peptides that areheld by this class 1 MHC– the peptides hereare being derived from a specific place in thecell, which is the cytoplasm. So the peptides arefrom the cytoplasm, so this is the sourceof the peptides, and I’ll tell you how thesepeptides are sort of loaded on to this MHC molecule. So the MHC moleculeis a sheath protein, so it’s changed on theendoplasmic reticulum, and its extracellulardomain is initially present in the lumen of the ER. And the peptidesare from proteins that are presentin the cytoplasm, and what happensto these proteins– and this exists forunfolded proteins, but also for proteins thatmight be ubiquitinated– is that they’re processedby the proteasome, which is this kind of a shredder-likefunction for proteins, and it cuts up the proteins intolittle snippets, or peptides, that can then be pumpedinto the lumen of the ER through this transporter, TAP.So these peptides canbe taken and transported into the lumen ofthe ER, and that’s where they’re loaded ontothe class 1 MHC molecule. But the source peptidesis from proteins that exist in the cytoplasm. They’re processedby the proteasome. So then, formerly you havea peptide-MHC complex, it can then be traffickedthrough the normal vesicle trafficking pathway all theway out to the plasma membrane of the cell where now thatpeptide will be displayed for T cadres to observe. And so the peptideshere, they’re processed by the proteasome– treated or cutby the proteasome– and then the typeof T cadre that’s going to look at theseclass 1 molecules– they are known as seedsCD8 positive T cadres. So this is the firstclass of MHC molecule. Because there is aclass 1, that wants there likewise must be aclass 2, which here i am. And so class 2 MHCs arefundamentally different in all of these properties. The serve sharedby these MHC molecules is they both showing peptideson the surface of the cell. So MHC moleculesdo spectacle peptides on the surface, which isknown as antigen presentation. But other than that, MHCclass 2 is pretty different. You identify the structureof MHC class 2 was similar tothat of class 1, but you see thatrather than having a heavy and a lightchain, here there are two chains that areroughly of equal sizing. And so these are encodedby different genes than the class 1 molecule, andthey encode different proteins.But the overall structuralsimilarity was similar, so there are twoIg domains, they’re proximal to the plasmamembrane, and then there’s this structure at the veryend of the MHC molecule, which has thisgroove in it which can hold a peptidethat would be displayed on the surface of the cell. And there, you investigate the grooveand you realise the peptide that is present in it. All privilege, so one big differencebetween class 1 and class 2 is that class 2 is expressedon a much more restricted set of cadres. So class 2 MHCs are expressedspecifically on specialized cadres known asantigen-presenting cells, and these antigen presentingcells include cells like B cadres, which are the onesthat I’ll concentrates on, but likewise phagocytic that can phagocytoseforeign substances– phagocytic cells– andthere’s another cell type called the dendriticcell, “whos also” an antigen-presenting cell. I’m going to focuson the B cells. So class 1 isexpressed everywhere. Class 2 is really expressedon these professional antigen-presenting cells. And the method that the peptides– the source of the peptidesand the action they’re made is also very different.So peptides for class 2 comefrom the extracellular infinite, and they are processedby lysosomal proteases. And so I’ll register you howthat inspections in caricature pattern. So for MHC class2, the peptides are from the extracellular seat. And so we’ve talkedabout practices that cells can take in material. One practice is throughendocytosis, right? So if this is myantigen, the antigen could be endocytosedby the cell, and now it’s in a vesiclethat’s represented in the cell. And so if youendocytose this protein, then it’s now in a vesicle, and one compartment that it can go tois the lysosome, where are these there arethese lysosomal proteases they can then chop up thisprotein into little snippets, or peptides.And so MHC class 2, again, is translated at the end ofendoplasmic reticulum, like all plasmamembrane proteins. But in theendoplasmic reticulum, you see the peptidegroove is blocked such that peptides derivedfrom the cytoplasm can’t interact withclass 2, but then is trafficked to a uniquecompartment which can combine with the section that hasthe peptides that originated from outside the cell. And then those can get loadedonto this class 2 MHC molecule, and then this can berecognized by T cells. But in this case, it is a– oh, I endocytosed my chalk. I need to get it back. Here. So in this case, it’s not a CD8T cell that’s recognize it, but a CD4 positive T cell. OK, so let me briefly reviewwhat I really went through, and evaluate the differencesbetween class 1 and class 2. So class 1 MHC is expressedon all nucleated cells, whereas class 2 ismuch more restricted, being expressed specificallyon antigen-presenting cells. The T cells that recognizethese two classifies are different. Class 1′ s recognized byCD8 positive T cadres. Class 2 is recognizedby CD4 positive T cadres. And the resources of the antigenis different in these two cases. The root of the antigenfor class 1 is the cytoplasm. For class 2, it’s theextracellular space. So the different MHCs aresampling different sort of ponds of proteins. And where thepeptide is loaded is distinct betweenthese two, which allows these distinctclasses to basically distinguished from thesources of the peptides that they’re loading. So for class 1, that’s in the ER. For class 2, it arisesfrom a vesicle locker that results fromendocytosis of an antigen from outside the cadre. All liberty. Now, the type of moleculethat recognizes this MHC peptide composite is the T cellreceptor, which I briefly outlined on Wednesday, but now we’re going to talk about itin much more detail.So the T cell receptor, or TCR– and I talked about its structurewhich is shown up on the slip, but I’ll simply drawmore simply here. If this is the plasma membrane, this is the cytoplasm, and this is theexoplasm facing down, then this T cellreceptor has two bonds. One is called the alphachain, and the second is called the beta chain. And each is comprisedof two Ig realms, which you participate up there. So the T cell receptorhere is in pink. You can see an Ig domainthere on one strand– Ig domain there. And you have another two Igdomains on the other subunit, and this receptor, the T cell receptor, recognizes antigens through itsvariable domain, which is here. And it’s fixing basicallyto the end of this receptor, so this is a sort of ribbondiagram of a organize for a T cell receptor. The plasma membranewould be up here. This is the end ofthe T cell receptor. And MHC is in light-green, andit’s holding a peptide here in yellow. And you can see how the TCR issort of interacting or docking to this MHC-peptide complex. So for the T cell receptorto interact and bind to MHC, you have to have aT cell receptor that recognizes thespecific conformation of the peptide that isbeing sort of extended away from the cadre. So let’s say this ismy T cell receptor, and I’m going around andsearching for cells that might want to look at this.Then if I had a T cellreceptor that was like this, it’s not going tobe able to stick to this MHC-peptide complex. However, if I had aT cell receptor that had the rightconformation, because there are different typesof T cell receptors, it might be able to dock onand stick to the peptide, and then the T cell is now stuckto the peptide-MHC complex, OK? So there are differentT cell receptors. There’s a diversityof T cell receptors, and they’re able to discriminatebetween different peptides loaded onto MHC. OK, so now, we have to thinkabout where such diversity of T cell receptors comes from. There’s a diversity ofTCRs, and luck for you, the mechanism that generatesthe diversity of TCRs is the same that generatesdiversity for antibodies.Now, Georgia queried a reallygood and really important question at the end oflecture on Wednesday, which is– she asked ifthis sort of rearrangement of gene segments in thevariable discipline of the antibody was due to splicingor recombination at the genomic locus. And the answer is thatit’s recombination at the genomic locus, andthat’s a very important point. So here’s a representation forthe beta series of the TCR. You can see that likethe B cell receptor, there’s a gene rearrangementin the genomic DNA that draws V, D, and Jsegments together to utter the variable series ofthe T cell receptor. So like the B cell receptor, there is a gene rearrangement, also known as VDJrecombination, and this is not splicing of the transcript.This is in the genomic DN–A a very important point, because by having this had occurred in thegenomic DNA, it creates an irreversiblechange in that genomic DNA such that allsubsequent cells that are derived from thatoriginal B or T cell are going to express theidentical B or T cell receptor. So it’s not splicing, but it’s a real sort of irreparable changeto the genomic DNA. So you have a diversity of Tcell receptors, but the T cell receptor is notthe only thing that enables the T cell tointeract with whatever cell is presenting the antigen. Thereare these other co-receptors which are important. So there are co-receptorson the T cell– this is on the T cell– and the co-receptorsare CD4 and CD8, and they’re expressed ondifferent subsets of T cadres. And these co-receptors–because it’s not sufficient for precisely the T cellreceptor to interact with a specific peptide, it also requires this co-receptor in orderto get an immune response.So the reasoning isthat if the T cell receptor and the co-receptorboth bind to the MHC, then you get a particular typeof response, so it is necessary to both. And CD4 cadres recognizethe class 2 of MHC. CD8 recognizes class 1 MHC. So you have these twodifferent subsets of T cells and they recognize thesedistinct MHC complexes. So my question for you is whatshould these CD8 positive T cadres do? To assist with that, you might want to look at where thepeptides are coming from that are presented on the class 1MHCs, which are going to be presenting specifically to CD8. So what should these do? What does it want if you have aclass 1 MHC molecule containing a peptide that looks foreign? Well, where do thepeptides come from? What’s that, Patricia? Patricia is right.They’re coming from the cytosol. So if you have foreign elementscoming from the cytosol, what might thatmean for that cell? Good, bad, irrelevant? What’s that? AUDIENCE:[ INAUDIBLE] PROFESSOR: What’s that? OK, Brett’s saying itneeds to be dealt with, and I entirely agree. Here’s one scenario–would be the scenario I proved you in thebeginning of class where you have some sortof intracellular parasite that is basically expending the hostcell for its own evil roles to produce more virusesor more bacteria. So if the immune cell hassome sort of indication that this is going wrong, another example is in cancer, because if you have oncogenicmutations in certain genes, then those could berecognized as foreign.And so an appropriateresponse might be to do something tothat cadre that would limit the expansion of the tumor. Or in the case of anintracellular parasite, you really need toterminate the cell so that you stem the tideof viruses that are going to be produced by that cadre. So the responseshould be to kill. So it was CD8 positive. If you have a CD8positive T cell, it reveals there’s somethingwrong inside that cadre, and the responseshould be to kill it. And these CD8 positiveT cells are known as killer or cytotoxic T cadres. So what happens if a CD8positive T cell recognizes a MHC class 1 peptidecomplex, then it secretes materials from insideit that perforate that cell and lead-in it toundergo cell demise. So it’s a way oflimiting an infection by killing the cadres thatthe virus or pathogen is employ to reproduction itself. OK, what about CD4 positive? What should be the responseof a CD4 positive T cell? Should it also kill? Should be like the T-1 000? No one get mycultural references.Yeah. Should it be the Terminator 2? No. Yes or no? Who thinks it should terminate? OK. Steven, can youtell us your logic? Why should it not interrupt? AUDIENCE: Becauseit’s a[ INAUDIBLE] B cadre from the same[ INAUDIBLE ]. PROFESSOR: What arethe MHC class 2 cells? AUDIENCE: Like, a Bcell or[ INAUDIBLE ].. PROFESSOR: Yeah. It’s not only a Bcell, it’s a B cell that recognizesthe foreign agent that you’re infected with. Yeah, Brett? AUDIENCE: So those B cellsare antigen presenting cells. They have the informationabout what is bad or “whats wrong” inprobably other cells? So like, oh, hey, wehave this information. You should go and muster. PROFESSOR: They’rebinding something that it recognizes as foreign, internalizing it, and then presenting bits ofthat foreign component on the outside of itself. Audience: Shoots the messenger. PROFESSOR: What’s that? It’s shooting themessenger, precisely. Yeah. So it would be an extremelybad idea for the CD4 positive T cell to kill what’spresenting the antigen, because you would kill theexact cell that you would need to fight that antigen, right? Now you have a B cell.It would be a B cell that’sproducing an antibody that really can produceantibodies that might be able to neutralizethat foreign attacker, and so you don’twant to kill it. You want to help it orenhance the B cell role. And so these CD4 positive cellsare known as helper T cells, and they improve B cell functionin a number of different ways. Oh, I should point outwhere this happens. So this sort of interactionbetween B and T cells happens in the lymph node, because in the lymph node, you have antigen-presentingcells, or even soluble antigens, cominginto these lymph nodes.And you also have Band T cells, and this is kind of like theB and T cell hangout to get sort of, like, interactions between these two different immune cell characters. And when you getsort of a B cell that presents an antigenthat’s recognized by a T cadre, then the T cell enhancesB cell function, and it does so in anumber of different ways. The first lane that it inducesa response in the B cell, known as affinity maturation. And this affinity maturationresults from a hypermutation of the variable domainof the antibody such that you get even morediversity, and such that a B cell can be selectedthat even has a tighter binding to the antigen. So for affinitymaturation, this is responsible for thetransition in binding from a more strong bindingto a tighter binding, which I talked aboutas being a difference between the primary infectionand the secondary sort of immune response, OK? So the antibodies get betterbecause of this B and T cell interaction and thisaffinity maturation process. One other thing that happensis that the B cells can induce different courses orisotypes of antibodies, and this is known asisotype switching. And so this is, again, the genomic locus for the ponderous chainof an immunoglobulin. You attend, here’s theVDJ segment, so it’s undergone VDJrecombination, and then what you visualize are thesedifferent blue parts here. Each of these are exons thatencode a different isotope for the antibody. So the first oneis mu, and so that produces IgM when that’s theone that’s proximal to VDJ.So if you have IgM, that’s theinitial commonwealth of the antibody, and that’s initiallymembrane bound and suffices as theB cell receptor. But each of thesedifferent constant domains, even though they’re notundergoing modification, they have differenteffector capacities and can do differentthings for the body. So for example, if youhad isotype switching and you had arecombination event that bring this gamma 2segment together with VDJ, that would produce theisotype which is known as IgG, and IgG is a highly secretedform of the antibody that is highly effective forbacterial infections because it’s secretedin the blood, and it’s able to neutralizebacteria and restriction the infection that way. But there are otherpossibilities, because you have all of thesedifferent potentials. And so you were able to get VDJtogether with this alpha, and that would producean isotype known as IgA. And IgA promotesmucosal immunity because it’s able to passthrough the epithelial linings. In addition, IgE isanother type of antibody, and the constant domains areconstant for each of isotypes, but they draft differenteffector runs. So IgG would be hittingbacteria by promoting phagocytosis of those bacteria. IgE, in distinguish, is especiallygood at dealing with insects, right? So if you have anintracellular– or not intracellular, but like, an intestinal insect or something like that, then IgE– its effector offices arebetter at dealing here with that. So this process ofisotype switching sort of allows the immune systemto adapt to tackle a particular type of pathogen. All right. The last acces in which Tcells enhance this function is by promoting thedifferentiation of B cadres into different types of B cells. One of those types of B cellsis known as a remember B cell, and the remember Bcell is a B cell that can last-place in thebody for decades, even if the antigenis not present.So this mediates sort of thememory of the immune plan. And so just to summarizewhat I simply told you, if you have a B cell and itrecognizes an antigen, which could be a protein, it wouldinternalize that protein via endocytosisand then process it so that it is possible displaypeptides from that antigen on its surface. And if that’srecognized by a T cadre, then that leads to aninteraction between the T and B cell that will lead to thesedifferent things happening, such as affinity maturation, isotype switching, so the red now would bea different constant chain on this same variable chain. So the variablechain doesn’t modify with the isotype swapping, so it’s still always able to recognize that antigen– it’s just recruitingdifferent effector purposes. And you can also getdifferentiation of B cadres into plasma cadres, which reallysecrete a ton of antibody, and therefore help thebody fight infection. Now “its important” becausefor a inoculation proved effective, you need to engage thisT cell response such that you have all ofthese things happening. So all of thesethings need to happen for an effective vaccine. So for an effectivevaccine, you can’t exactly activate the humoral sideof the immune structure. You have to activateboth the humoral and the cell-mediated sidessuch that they interact in order to enhance the immune response. All right. Now I’m going to move onand talk about a big problem that the immunesystem has, which is that it needs to somehowbe able to discriminate between soul and foreign, right? And so if you have yourimmune system realise an antigen that isnatively part of your form, that results in anautoimmune cancer. So there’s a balancein the immune arrangement between toleratingantigens or attacking them, and if it’s attacking a nativeantigen, then it’s autoimmune. And this is a hugeproblem because, if you think about it, becausewe’ve talked about the B cell receptor, the antibody, andthe T cell receptor, right? Our people are generatingtens of millions of these receptors thatare diverse and can recognize different molecules. So our torso is generatingtens of millions of antigen receptors, andit does this constitutively, so that means that it’sjust make it automatically.You don’t even need to beinfected for this to happen. This is just part of thedevelopment of B and T cells. OK, so it’s constitutive, doesn’t involve infection– constitutive. In add-on, it’stotally random. Your body could generate anysort of compounding of V, Ds, and Js, and it couldmutate in a certain way that it’s likely that at somepoint during your lifetime you’re going to generatea receptor that recognizes a native protein in your mas. So it’s totally random– at least what the sort ofrearrangement of VDJ imparts. That process isconstitutive and random. So I really just wanted to pointout various cankers that are caused by autoimmunity, and I’ve distinguished them based on whetherthe disease involves the generation of antibodiesthat recognize soul or T cadres that recognize self. So for antibodies, there’s adisease, myasthenia gravis, which an individual’s–individuals generate an antibody against a receptorfor a neurotransmitter, acetylcholine. And acetylcholine isthe neurotransmitter which is predominantly involvedin mailing signals from a motor neuron to a muscle, and therefore antibodies thatinhibit this receptor result in muscle weakness.Now self antibodies canalso to be translated into diabetes, and individuals candevelop antibodies that recognize and inhibitthe insulin receptor, and this leads to insulinresistance and diabetes mellitus. Some examples of Tcell interceded infections are– if you recall back inthe beginning of the month, when we talked about electricalsignaling in neurons, I told you aboutthe myelin sheath and how this increasesthe speed of the action potential along that axon. And if T cells attackthe myelin sheath, then it obstructs this processof electrical signaling, and that results in adevastating sicknes, which is multiple sclerosis. Autoimmune disease involving Tcells also involves diabetes, and if T cellsattack and destroy the islet cadres of thepancreas, that is something that obstructs the body’sability to produce insulin, and that resultsin sort 1 diabetes.So I’m sure manyof you know people with these types of sickness, and they’re undoubtedly of significant impactboth in this country and around the world. So the problem for the cadres inour body and the immune organisation is that the immune systemhas to have some sort of way to distinguish betweenself and foreign. So how is it that theimmune plan does this? And too, it has tohave different responses to self-recognition versusforeign recognition. So what should theimmune system’s response be if there is aself identification? What should it doto the cells that recognizes a native protein? Rachel? AUDIENCE:[ Inaudible] PROFESSOR: It coulddelete that cell. What Rachel said is youshould get rid of it. And so one path to thinkabout this process is there’s a bit of a Darwiniannatural selection going on in the body, and if thereis a self recognition, then there should be a negativeselection against that cadre, so there should benegative selection. This cell should be moreunfit, whereas if it’s obviously foreign, then thereshould be positive selection. This B cell should be more fit. And what Rachelsuggested is to get rid of the cell, which is a greatidea, because if you kill off the cell then you won’t generateany more cells that have that identification against self. So negative selection ismediated by apoptosis and cell death. And positive pick could beboth the activation of the cadre and also its proliferation. As you identify up on the slidethere, that orange cell– if it was recognizing a foreignantigen, would get activated and it would experience amonoclonal stretch. All the cells resultingfrom that stretch would convey the same antibodyand therefore recognize that antigen, sothis would result in cell division or expansionof that population of cadre. So now we know what to dowith self versus foreign, but how is it thatwe distinguish between self and foreign? So how does the immune systemdistinguish ego from foreign? And there are currently severalmechanisms to do this. The first is that the organs– the lymphoid organs– whereare these B and T cells mature and experience thesegenomic rearrangements are principally protectedfrom foreign agent. So there are basicallyonly self antigens in the generativelymphoid parts. These are the lymphoidorgans were B and T cadres are being generated. So the generativelymphoid organs would be the bonemarrow for B cells and the thymus for T cells. Therefore, if a B or T cell– if its receptorengages with something very tightly duringits development, that’s a signal forthe immune system to delete and killoff that cell. So if you get selfrecognition here, you get apoptosis anddeletion of that cell. The second nature that thebody is able to distinguish is that it responds toantigens precisely when there is aninnate immune response, or if it respondsbetter when there is an innate immune response. So you can think of it like acoincidence detector, right? If you have an immune celland it recognizes an antigen, and there’s also aninnate immune response, that’s a strong indicationthat this is foreign.So this would indicate”foreign” to the immune system. If there is antigenonly and the body is not mounting an innateimmune response, it’s much more likelythat this will generate a robust immune response, andthis is the immune system’s signal that thisis a self antigen. This is also importantfor vaccine development because in mostvaccines, in addition to having some antigen that’sa part of the virulent worker, there’s also something calledan adjuvant, which is basically something that activatesthe innate immune system.So the adjuvant activatesthe innate immune response, and that’s importantbecause if you only had the vaccine withjust the antigen, there wouldn’t be nearlyas robust a response. So you need both to activatethe adaptive immune organization, but too the innate immunesystem to truly get a robust response. So I want to end by talkingabout this year’s Nobel Prize work, and it involvesanother mechanism that mostly preventsautoimmunity and downregulates the activity of theseT cadres, and that involves another type of– we’veonly talked about activating receptors on the T cadre, right? The T cell receptor, CD4, CD8– they’ re activating receptorsfor the T cell receptor, but there are alsoinhibitory receptors that are on the surface of T cells. So inhibitory– we’lljust call them receptors. One is called CTLA4 andanother is called PD1. Their identifies are not terriblyimportant, but what they do is they keep theimmune system in check. And we’ve talked alot about signaling and how signalinggets activated, and often a step in signalingis once you get the signal mail, and it’s been sent, thereis, like, a negative feedback that then turnsoff the signal such that there’s signal termination.So you often have sometype of signal expiration. That highway, you don’t have justa constitutive activating of the signal, which in this case would be sort of inflammationand an immune response, and one or both ofthese is involved in sort of keep theimmune method in check and stopping it after youget that initial reaction. Now, the reasonthis is so important and why James Allisonand Tasuku Honjo won the Nobel Prize isthey had the idea to use this as atherapy for cancer. And it turns out thatsome cancer cells can express the ligand forthese inhibitory receptors such that they can avoid theimmune system from recognizing the tumor. So this would be one case wherethe tumor cell is expressing the ligand for PD1, and thatinhibits the affair of this T cell receptor so that itdoesn’t kill the tumor cadre, and that leads to theexpansion of the tumor so the tumor can expandin an unchecked way.And what James Allison andTasuku Honjo resolved is that if you blockthat inhibitory receptor, then you sort of uncheck theresponse of the immune organization such that theseimmune cadres are now able to recognize thetumor cells and kill them. So by kind of blockingthe inhibitor, you now have T cells– these areCD8 positive T cadres that are killer cells– they will now recognize theseT cells and kill them off. So there’s what’s knownas an inhibitor obstruction because you’reblocking the inhibitor, and these inhibitors areantibodies that recognize these inhibitory receptors, andthey’re now being used to treat some forms of advanced cancer.And so this is somethingthat the cancer field and immunology fieldsare both really excited about. What might be one complicationwith this type of management? If you get rid of theinhibitory receptors, what might be a consequence? Yeah, Steven? AUDIENCE: Then you couldrecognize other self cells that restraint[ INAUDIBLE ]. PROFESSOR: Yeah, youget autoimmunity. That’s exactly right. So one of the downsidesof this is that– one of the side effects isthat you can have cases with an autoimmune reaction. So it’s not the magicbullet, but it’s a step in the right direction. All freedom, we’llsee you next week.
