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0:07
My name is Hidde Ploegh. I'm an investigator at Boston Children's Hospital in the program of Cellular and Molecular Medicine. I will present two talks today. The first one provides you with a more general introduction to certain aspects of the immune system. And in the second half of the talk, I'll speak about some evolutionary anomalies in the immune system that we've been able to leverage into a new class of tools that I think will be of more general interest.
0:36
So, let me begin by giving you an introduction of host defense. We generally consider host defenses composed of three layers. Mechanical and chemical defenses, depicted in this diagram, as line 1, probably hold at bay 98% or more of viruses and pathogenic bacteria. But because these organisms come equipped with special tricks to cir... circumvent these barriers, we have a backup system. This is the combination of innate and adaptive immunity.
1:11
Layer 2, innate immunity in this cartoon, should be considered the rapid-deployment forces of the immune system. They can distinguish between pathogenic entities such as bacteria and our own tissues, but do so with a limited degree of specificity. The nice thing is that they respond very quickly. And so, should defenses of the mechanical and chemical nature fail, usually innate immunity deals with the ensuing problem.
1:41
But given the sophistication of pathogens and the tricks they've evolved, some of these require stronger measures. And for that reason we have adaptive immunity kick in. This is a time-consuming process, but it allows us to distinguish, truly with pinpoint precision, between pathogenic microorganisms and our own tissues. So, what I'll do in the next segment is to describe one particular aspect of the adaptive immune system, because this will become relevant when we discuss,
2:12
in the second part of my presentation, some of the unusual properties of antibodies made by other vertebrate species. This is an amplification of the cartoon that I've just shown you, and it provides a little bit more specificity. You have the pathogens coming in. They come equipped, as I've said, with enzymes that would allow one to break down these mechanical defenses. They can inactivate some of these chemical defenses. And so when layer 1 fails, innate immunity kicks in.
2:44
And here we have a combination of cells -- such as macrophages and dendritic cells -- as well as molecules -- proteins of the complement cascade and hormone-like substances referred to as cytokines -- that collaborate to provide protection. In turn, the output of the innate immune system synergizes with adaptive immunity. And this layer of defense really becomes important when innate immunity fails. So, the products elaborated in the course of an innate defense prime the pump,
3:16
so to speak, and facilitate the ensuing adaptive response. This comprises types of lymphocytes that I'll discuss in a moment. But it's really the synergy between innate and adaptive immunity that makes a key contribution to host defense. If we look at the kinetics with which these processes unfold, it recapitulates some of the items that I've already spoken to you about. Innate immunity consists of molecules such as type-1 interferons, natural killer cells...
3:47
and these kick in literally within hours to days of exposure to the pathogen. If we look at what happens to the virus titer -- if we deal with, say, an influenza virus infection -- we see that innate immunity can rapidly reduce the number of circulating virus particles, albeit not to zero. And it is at this point that adaptive immunity must kick in. We have virus specific CTLs; the abbreviation stands for cytotoxic T lymphocytes.
4:16
And we have antibody titers that rise as the infection is being resolved. In a first exposure, the rise in antibody titers is relatively modest. And in a phenomenon referred to as immunological memory or recall response, the secondary exposure rapidly leads to massive induction of both antibody titers, we have memory killer T cells that kick in, and it's the combined action, again, of these antibodies and T cells that manages to control the infection.
4:54
If we think of where these processes occur in the human body, we must consider the circulatory system, which includes arteries and veins. It's the high arterial pressure that allows some fluids to leave the bloodstream, which must be returned to the circulation in the form of lymph. This lymphatic fluid is filtered through specialized structures called lymph nodes. And it's really in these lymph nodes that the immune responses of the adaptive type take place.
5:23
We should consider the circulatory system as a means of trafficking. It's the vehicle via which lymphocytes, from their site of origin, arrive at their final destination. And so, by monitoring what happens in the bloodstream, we can only get a transient snapshot of what a real immune... immune response looks like. So importantly, all of the important events that start an adaptive immune response take place in specialized lymphoid structures called lymph nodes.
5:56
On the right, you see the organization of the lymphatic structures in a human. The little ball-like structures are the lymph nodes, through which lymph fluid is filtered. And it's really in these specialized structures that adaptive immunity is initiated. One important cell type that we will revisit later on in this presentation are so-called dendritic cells, thus named because they have spines that very much resemble what one finds on neurons.
6:27
And these dendritic cells are positioned throughout the body. They are really the first point of encounter of a foreign invader with the immune system. And it's the ability of dendritic cells to assess the presence of an invader, to then process that information, and present it to the appropriate cell types within the immune system that is responsible for proper orchestration of these immune responses. If we ask, what cell types contribute to adaptive immunity?
6:57
They are really the lymphocytes that I'll speak about most. If we consider the origin of lymphocytes, they all derive from a stem cell that arises in the bone marrow. These so-called hematopoietic stem cells give rise to all bloodborne cells, including platelets, red blood cells, and so forth, as shown on the left branch of this slide. But importantly, for the remainder of the discussion, will consider mostly the lymphocytes.
7:21
They originate from a common lymphoid precursor and, through a series of carefully orchestrated differentiation steps, they give rise to both B lymphocytes and T lymphocytes, thus named because of their bone marrow and thymic origin, respectively. The output of B lymphocytes are so-called antibodies or immunoglobulins, a diagram of which is shown in the top. And I'll return in some detail to the structural features of this class of molecule.
7:48
But let me point out that these antibody molecules, or immunoglobulins, exert a number of functions that can contribute to protection. First of all, they enhance phagocytosis. This is the process by which the dendritic cells that I've just mentioned can acquire particulate matter and process it to cells of the immune system. Antibodies can also assist the function of elements of the innate immune system. On the bottom left, I've shown natural killer cells.
8:16
They can bind immunoglobulins through receptors specific for them. And once their union has occurred, they can assist in the killing of targets to which the antibody is bound. On the top right, you see yet another mechanism by which antibodies can confer protection. And this is complement-mediated cytotoxicity. In addition to immunoglobulins that circulate in the bloodstream, there's a class of proteins called the complement proteins that, when properly activated, can directly exert
8:46
a cytolytic effect, either on bacteria or, as shown in this particular example, on tumor cells. And then finally -- and this is one of the earliest discoveries as far as immunoglobulin function is concerned -- immunoglobulins or antibodies can neutralize bacterial toxins. They can bind to virus particles. And by covering the surface of these structures, render them pretty much innocuous. So, these are the many functions of immunoglobulins.
9:16
And the one that I've left out so far is the one on the top left. We also have practical applications of immunoglobulins. And spectacular recent examples include the immunotherapy of cancer. And, as I'll show in the second half of my talk, we can make derivatives of these antibody fragments and use them for purposes such as imaging of immune responses, non-invasively. So, what about the structure of immunoglobulins? As this cartoon illustrates, they are proteins abundantly present in serum.
9:48
They're glycoproteins composed of two identical heavy chains, in dark blue, and two identical light chains, in light blue. The heavy chains are glycosylated, and the light chains and heavy chains are held together by disulfide bonds. Biochemists would like to shrink the immunoglobulin molecules into units that retain the capacity to bind antigen. And for this purpose, proteolytic digestion has been used.
10:12
On the bottom left, you see the products that result from digestion with the protease papain. It results in the release of fragments that are so-called Fab fragments. They are monovalent and retain the capacity to bind antigen. If you wish to retain the capacity of bivalent binding, an intrinsic property of the immunoglobulin molecule, pepsin digestion may be used. And this allows the two antigen-binding fragments to remain linked through disulfide bonds, as indicated on the bottom right.
10:42
If we look at the diversity of immunoglobulins as they occur in the typical mammalian species, there is massive diversity in structure and function. I won't have the time to discuss all of these diverse functions, but I do want to highlight a few of the salient structural differences. We have here this massive pentameric structure of a class called immunoglobulin M or IgM. We have a version of immunoglobulins that's found in secretions such as tear fluid,
11:10
held together by an unusual protein called the J chain. We have the IgE molecule, implicated in allergic reactions. And what most of you are probably familiar with are the immunoglobulins of the IgG classes, of which several subclasses exist. Now, when we look at the ability of an antibody molecule to bind a foreign substance, also called an antigen, we realize that the immunoglobulin contacts the antigen at the very tip of this Y-shaped structure.
11:42
And because structural biologists have been able to solve the three-dimensional structure of antibody fragments in complex with antigen, we know at atomic resolution exactly how these acts of binding occur. So, in this box here, you see at higher magnification the typical mode of interaction of an immunoglobulin with its antigen. You'll realize that the immunoglobulin, composed of two identical heavy chains and two identical light chains,
12:08
uses elements of both to achieve this specific recognition. So, in light blue, the variable region of the light chain; in dark blue, the variable region of the heavy chain. And it is through the tips of these very subunits that interactions occur with the antigen. These include hydrophobic interactions, salt bridges, van der Waals interactions... a perfectly complementary surface is created to confer specificity. And we know that antibodies can achieve a degree of specificity that allows them
12:39
to distinguish between molecules that differ in as little as one proton. The presence or absence of a hydrogen atom can make all the difference -- whether or not an antibody recognizes its target or not. So, if we consider the ability of the immune system to mount an immune response against pretty... any... pretty much any foreign substance we throw at it, we must ask the question, how does the immune system achieve this remarkable result?
13:07
So, first of all, biochemists, without recourse to any molecular genetic tools, accumulated large numbers of sequences of immunoglobulin proteins. And this allowed them to relate the primary structure -- that is to say, the amino acid sequence of the immunoglobulin variable regions -- to their antigen-binding properties. And by aligning multiple sequences of either the heavy chin or light chain variable regions, several salient features emerged.
13:39
The so-called hypervariable regions, indicated in red, are precisely those regions in the molecule that contact the antigen. And if one compares a large number of different sequences, that is also where the majority of sequence diversity is concentrated. This is not to say that other residues cannot vary, as is clear from the gray bars, which indicate the variability index -- the extent to which different variable regions might
14:05
differ from one another -- but the bulk of the variation occurs in these three hypervariable regions, also called complementarity-determining regions because that is exactly where the binding of the antigen occurs. Now, if one were to consider a million different antigens against which we would like to raise an antibody, and you calculate the amount of genetic information required to encode that information in the germline of an organism, you quickly reach the conclusion that
14:35
you run out of sequence space. There is simply not enough DNA to encode, at the DNA level, the structure of a million distinct antibody fragments. And this is a question that has puzzled immunologists for decades until, in the '70s, the molecular mechanisms by which diversity is generated became to be understood. It turns out that immunoglobulin genes are, like many eukaryotic genes, genes in pieces. But there's an additional element of surprise, here.
15:08
In fact, when we create a functional immunoglobulin gene, it's not just about introns and exons that require splicing to create a functional messenger RNA. The very cells that produce these immunoglobulins reshuffle their genetic information. This is called somatic gene rearrangement, and it accounts for much of the diversity of the immunoglobulins as proteins. On the top of this diagram, you'll see our current understanding of how the light chain locus operates.
15:38
In mice and humans, there are two types of light chains called kappa and lambda, and I'll confine myself to a quick description of what happens for the kappa light chain. We have a battery of variable region sequences, separated by intervening DNA, followed by so-called joining segments, and, at some distance downstream of it, the remainder of the kappa light chain, the so-called constant region. In the course of B cell development, somatic gene rearrangements occur, and this allows
16:07
juxtaposition of a randomly chosen V gene element with a randomly chose chosen J segment. And it's not until this rearrangement process is complete that we arrive at a functional light chain. You'll notice that I've indicated the presence of an enhancer. The promoters that drive expression of a functionally rearranged heavy chain do not come within controlling distance of these enhancers unless and until somatic gene rearrangement has occurred. So, the rearrangement process achieves two things.
16:37
First, it creates a functional unit that can be transcribed and translated into what we know to be a light chain. And second, its expression, its transcription, is controlled by an enhancer, the function of which requires the rearrangement process. For the immunoglobulin heavy chain locus, the situation is somewhat more complex. In addition to this battery of these V segments and J elements, we have interposed a battery of so-called diversity elements.
17:06
And in this case, the rearrangement process makes use of V, D, and J rearrangement to arrive at a functional heavy chain variable region. There is, again, an enhancer, the reach of which does not extend into those V genes that have yet to rearrange. And it's only upon completement... completion of the rearrangement process that the VDJ combination is placed within controlling distance of this enhancer to enable expression of a functional heavy chain.
17:39
This process is perhaps best compared to the one-armed bandit. Think of V, D, and J elements as three independently spinning wheels on a slot machine. The B cell, in the course of development, pulls the handle, and some random combination of these Vs, Ds, and Js emerges. This is not the whole story. In this particular diagram, I've recapitulated what I've just told you -- for the heavy chain locus, a battery of these Vs, Ds, and Js.
18:09
And in the course of B cell development, these rearrangements to which I referred occur in highly ordered fashion. First we have the D-to-J rearrangement. And what I've indicated here by this little segment of rainbow-colored material in between is a phenomenon called junctional imprecision. When a D and a J element are juxtaposed, the act of recombination itself produces some imprecision at the joint, adding and subtracting nucleotides in an unpredictable fashion.
18:40
And as you might imagine, if you disrupt the reading frame, you have what is called a non-productive rearrangement. If you add multiple nucleotides, you can affect the primary structure of the final product. And so this imprecision in the course of V, D, and J rearrangement contributes to diversity of the final product. Not only do we see this junctional imprecision when Ds and Js rearrange, it also applies when Vs are brought in to hook up with the newly generated DJ combination.
19:13
And if that weren't enough, there is an enzyme called terminal deoxynucleotidyl transferase or TdT. And this enzyme, in template-independent fashion, adds random nucleotides whenever Ds and Js, or Vs and Ds, are joined together. This massively expands the diversity of the final product. And so if we consider the problem of antibody diversity, it is the combination of a random choice of Vs, Ds, and Js, but that information is strictly germline encoded.
19:42
But the very act of somatic recombination introduces an element of imprecision whenever joining occurs. And this allows massive expansion of diversity of the immunoglobulin variable regions. So, this slide summarizes much of what I've told you already. In this case, for the light chain, I've indicated the positions of variability. On the bottom, you see these hypervariable regions to which I made reference. And the constant region, as the name suggests, is invariant in sequence and doesn't
20:14
make contact with antigen. It serves to mediate interactions between the various building blocks of the immunoglobulin molecule itself. These ovals are referred to as immunoglobulin domains, and they all share a conserved sequence. If we consider the different manifestations of immunoglobulins as they occur on the surface of a B cell, we realize that there's an important cell biological distinction to be made.
20:42
B cells make both membrane-bound immunoglobulin, and that very same immunoglobulin can be secreted as well. This is a process that's controlled by alternative polyadenylation. Depending on which poly-A addition site is used, the B cell either produces the secreted version or the membrane-bound version of that one-and-the-same immunoglobulin. This foreshadows the important role of the B cell receptor in perceiving antigen and
21:08
allowing B cells to expand, but also to allow that very same B cell to release immunoglobulins into the bloodstream, where they can exert their effect, for example, by neutralizing a virus. The B cell receptor also plays a key role in orchestrating the processes that I've just summarized. So, in the absence of a functional heavy chain rearrangement, B cells fail to complete development. The discrete developmental stages are characterized by the presence of so-called surrogate light chains,
21:35
in this diagram depicted as VpreB and lambda-5. And only when those subunits all come together and form a properly assembled pre-B cell receptor does the B cell enable rearrangement of the missing piece, which is the light chain. So, this pre-B cell receptor, depicted on the left, is a necessary condition for B cells to engage light chain rearrangement. And it's only when all these processes are executed perfectly that we arrive at
22:05
a fully assembled B cell receptor at the surface of a B lymphocyte. You'll notice these little red and yellow stubs. These are coreceptors, referred to as Ig-alpha and Ig-beta. And they're absolutely crucial, because the B cell receptor itself -- the immunoglobulin subunits -- lack the cytoplasmic tails required for signal transduction. It's the non-covalent association with these accessory subunits -- Ig-alpha and Ig-beta --
22:32
that allow so-called immunoreceptor tyrosine-based activation motif, or ITAMs, cytoplasmically disposed, to recruit the requisite kinases that initiate internalization, proliferation of B cells that properly engage the antigen, and so forth. So, to summarize, this would be the structure of a B cell receptor as you would find it on the typical resting B lymphocyte. A membrane-bound version of the IgM molecule in non-covalent association with these accessory subunits, Ig-alpha and Ig-beta.
23:03
And it's through these accessory subunits that B cell receptors fulfill most of their functions. There's an added layer of complexity. And we'll have to use that when we discuss, in the second part, the unusual attributes of certain antibody molecules made by camelid species, and this is a phenomenon referred to as class switch recombination. Recall that at the outset I referred to the different classes of immunoglobulins --
23:28
the hugely complex pentameric IgM all the way down to the more simple IgG molecules. It turns out that a given VDJ combination can be put in juxtaposition with the information that provides the IgM molecule, the so-called new chains. And by a process called class switch recombination, that rearranged VDJ cassette can be placed upstream of whatever constant region you might require to execute the necessary functions.
23:57
This class switch recombination requires the involvement of the other major class of lymphocytes, this... the T lymphocytes or T helper cells. And there are accessory molecules such as the cytokine, IL-4, and enzymatic functions, activation-induced deaminase expressed in the B lymphocyte, that are an absolute prerequisite to execute the class switch recombination. So at the end of the day, you might end up with an IgG-producing B lymphocyte which takes
24:24
this VDJ cassette and places it in juxtaposition, in my example, with the gamma-2 constant region. In yet another example, you might take that very same VDJ combination and instead hook it up to the alpha constant region, so that you may suit... that so that you may produce this secreted version of the IgA molecule. Now, how... how is all of this arranged? It turns out that we have a detailed molecular understanding of how this somatic rearrangement process,
24:56
as well as the class switch recombination, occurs. And unlike the enzymes involved in putting together V, D, and J elements, class switch recombination requires the activity of activation-induced deaminase, expressed in B cells only when properly contacted by T helper cells. In a looping-out reaction, the rearranged VDJ combination is put in juxtaposition with whatever constant region the B cell demands at that point in time.
25:26
And by physical excision of the intervening DNA, we may now connect the functionally rearranged VDJ combination to whatever constant region we require. Now, importantly, I refer to the role of helper T cells to execute this reaction. To understand a little bit more about how these T cells operate, let me give you the following information. The professional antigen-presenting cells -- think of the dendritic cells which I showed at the very outset --
26:00
may acquire antigen, a foreign substance, by a process called phagocytosis. Once the phagocytosed antigen has been internalized and delivered to the appropriate endocytic compartments, these antigens are attacked by proteolytic enzymes and converted into short peptide fragments that will be displayed on the surface of the so-called antigen-presenting cell. There's a special class of molecules involved in this process. These are the products encoded by the major histocompatibility complex,
26:30
to which I'll return as well. And it's really the combination of these unique peptide- MHC combinations that will be recognized by T lymphocytes by means of antigen-specific receptors. The B cell is a specialized case. It too can bind to antigen by virtue of the fact that expresses, at its surface, the B cell receptor for antigen. The B cell receptor for antigen is really the high-affinity capture device that
26:59
allows the B lymphocyte to probe what's in the external environment and bind only those protein antigens, or other foreign substances, for which it is specific. It does so by virtue of what we call an epitope. This is a structural feature of the antigen itself that can be seen by the B cell receptor. Now, B cells can internalize the B cell receptor when complexed with antigen. And by the same mechanism that I've just described, proteolytic activity will chop up the foreign protein
27:29
into short synthetic fragments, which are bound by these MHC products and presented on the surface of the B lymphocyte. It is the T cell that now recognizes, by means of its antigen-specific receptor, the unique combination of peptides derived from the original antigen, presented by products of the MHC. And the key concept to understand here is that the features of structure that allowed the B cell to recognize antigen in the first place may well be distinct from the fragments
28:00
generated from that antigen and presented via MHC molecules to T lymphocytes. This phenomenon is called linked recognition, and it ensures that only those B cells that have acquired antigen and present peptides derived from it to appropriately specific T cells that an antibody response can ensue. So, to integrate all of this, and without going through the details... on the far left, you'll see dendritic cells acquiring antigen and presenting it to T helper cells.
28:30
In the right half, you'll see B cells acquiring antigen and presenting peptides to T cells of appropriate specificity. And when all is said and done, we have a productive interaction between the T helper cell, which is antigen specific, and the B cell, that is antigen specific. And so this is how we can orchestrate an immune response. I mentioned the fact that there are two major classes of lymphocytes: the B lymphocytes,
28:55
which we just discussed, and T lymphocytes, which as we saw provide necessary help and also generate so-called killer T cells, or cytotoxic T cells. They have antigen receptors very much like the B cell receptors we discussed. And they make use of very similar rearrangement processes, in fact employing the exact same enzymatic machinery. So, the T cell receptor, like its immunoglobulin counterpart, is composed of two subunits: alpha and beta subunits.
29:25
And they, like their immunoglobulin counterparts, make use of V-to-J and V-to-DJ rearrangements, as diagrammed in this cartoon. Each element is flanked by the appropriate recognition signal sequences, features of structure that are shared with the immunoglobulin variable regions of the heavy and the light chain. Now, T cells, as I've said, recognize antigen not in solution but bound to the products of the major histocompatibility complex.
29:53
As diagrammed in this cartoon, you see a T cell receptor with its two subunits engaging a class-I MHC product, thus named because it spans the lipid... lipid bilayer only once. And these MHC products present these short snippets of foreign protein to antigen-specific receptors on T cells. In the second part, I'll have a few words to say about these so-called co-stimulatory or checkpoints. These are molecules that can fine-tune immune responses, and either enhance or inhibit
30:24
immune recognition by T lymphocytes. Now, the MHC products are unique in structure because, notwithstanding the fact that they are of unique and fixed sequence, they can nonetheless bind a vast diversity of peptides by virtue of the fact that the architecture of the peptide binding pocket is designed such that many peptides of different sequence can fit into one-and-the same peptide binding pocket. The overall global structure of a class-I MHC product is composed of a heavy chain
30:58
in non-covalent association with its light chain, beta-2 microglobulin. And it's this assembly that creates the peptide binding pocket -- this is the top view of the very same molecule shown here -- into which peptides bind for presentation to these antigen-specific receptors. The way in which this system functions is that T cells are test-driven on MHC products that present peptides from our own self proteins, which you ideally would like to ignore.
31:28
And it's not until a stressful situation such as cancer or infection occurs that new peptides derived either from pathogen-specific proteins or tumor-specific antigens make their appearance. So, the immune system is taught to ignore peptides of our own proteins. And what remains at the end of the day is a repertoire of T lymphocytes uniquely capable of recognizing peptide-MHC complexes that differ from our own self-MHC products.
32:00
If you think of an infectious situation, in the absence of any immune recognition, unopposed infection might result in the organism’s death. We have lytic infections. We have massive virus production. And it is for this reason that we have components of the adaptive immune system, to fight specifically these kinds of events. I've mentioned the fact that antibodies can neutralize virus particles in the circulation. That is one means of protection.
32:29
I've indicated the existence of so-called killer T cells, the CD8-bearing T lymphocytes. CD8 is a glycoprotein marker uniquely confined to these killers. And by means of their antigen-specific receptors, they recognize class-I MHC products that present, for example, viral peptides as in this example. But because many pathogens have replication times vastly shorter than the host, they can acquire mutations that allow them to elude immune attack.
33:00
And that's depicted by the transition of this somewhat innocuous pink virus to the nasty red. Many of these viruses do so by, for example, altering expression of class-I MHC products, and that also happens to be one of the mechanisms by which cancerous cells can evade detection by T lymphocytes. If you eradicate expression of class-I MHC products, you're essentially invisible to the cytotoxic T lymphocyte, and that gives you the upper hand in terms of virus production
33:31
or, in the case of a cancerous cell, replication. Now, we know a great deal about the molecular details by which the class-I proteins acquire their peptide cargo. From a cell biological perspective, this is a very unusual and interesting series of reactions. And it focuses on the function of the ubiquitin pathway. Proteins in the cytoplasm are modified by ubiquitin in an enzymatic cascade that involves these three classes of enzymes: E1s, E2s, and E3s.
34:00
And having modified our protein with multiple ubiquitin molecules, now these proteins are poised for recognition by the proteasome, which in a highly processive fashion destroys these proteins and produces peptides capable of being recognized by T lymphocytes. The problem, however, is the fact that the entire machinery for the generation of peptides is located in the cytoplasm, whereas the molecule charged with antigen presentation lives in extracellular space.
34:28
So somehow we must deliver peptides to extracellular space. And this is the function of a dedicated transporter referred to as the transporter associated with antigen presentation, or the TAP protein, indicated by this array of helical segments here. Once peptides are translocated into the endoplasmic reticulum, they become part of a nascent class-I MHC product, which itself requires the action of a panoply of chaperones to ensure its proper folding.
35:01
But when all is said and done, we make this peptide-MHC complex, which is then free to travel to the cell surface. And as I've suggested in the preceding slide, viruses are masters of deception. They've evolved numerous countermeasures with which to frustrate this process of antigen presentation. And here's just an example taken from herpes viruses, one class of pathogens that once you acquire them stay with you for the rest of your life.
35:26
We have proteins that in... such as pp65 that involve... that interfere with ubiquitylation of possible targets. The virus that is the causative agent of mononucleosis, Epstein-Barr virus, produces a protein that renders viral products insensitive to proteolytic digestion by the proteasome. We have other herpes virus-encoded proteins that impede peptide translocation into the endoplasmic reticulum, detain class-I molecules at the site of synthesis,
35:58
or even reverse the process of membrane insertion and target those very same MHC products for proteasomal degradation. The process is more complex than this. We have meanwhile figured out some of the details. This is the mating dance between the viral protein US2 and the class-I molecule it destroys. And in a process referred to as retrotranslocation, a newly assembled class-I heavy chain is sent back to the cytoplasm for proteasomal degradation.
36:27
This is just one example of the many tricks viruses can use to frustrate adaptive immunity. And such interference may apply to other surface proteins, cytokines released from the cell, aspects of innate immunity. I need to emphasize the fact that the constant interplay between the immune system, which exerts a selective pressure, and pathogens, which have the capacity to rapidly evolve, results in this per... perpetual chess game between host and pathogen.
36:57
Much of this work enables cell biological explorations that would be difficult to achieve otherwise. And to put some molecular detail on this particular cartoon, this would be our current understanding of how this complicated machine operates. We have this centrally positioned class-I MHC product and a host of other cofactors that together ensure that this class-I protein in a virus-infected cell can be extracted from the endoplasmic reticulum and ultimately targeted for proteasomal degradation.
37:27
So, after this whirlwind tour of the immune system, let me return to where we started. We have a multi-layered immune defense system, of which the mechanical and innate immune defenses are probably the most important on a daily basis. But once these systems fail, adaptive immunity kicks in. And the remarkable precision with... with which the adaptive immune system can recognize antigens has allowed the explorations which I've tried to summarize in the preceding thirty minutes or so.
37:58
Key features: ability to distinguish between structures that differ by very little -- as few as an atom, perhaps; the ability to respond rapidly; and the ability to adjust the specificity of the ensuing response to whatever the needs of the day may be. In the second part of my talk, I will highlight one specific element of this adaptive immune system. And we'll see how this can be leveraged into tools that might be useful, both for basic cell biology as well as for biomedicine.
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