Immune Biology

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Immune Biology - II
Like antibody responses, T-cell-mediated immune responses are exquisitely antigen-specific, and they are at least as important as antibodies in defending vertebrates against infection. Indeed, most adaptive immune responses, including most antibody responses, require helper T cells for their initiation. Most importantly, unlike B cells, T cells can help eliminate pathogens that would otherwise be invisible inside host cells. Much of the rest of this chapter is concerned with how T cells accomplish this feat. T cell responses differ from B cell responses in at least two crucial ways. First, T cells are activated by foreign antigen to proliferate and differentiate into effector cells only when the antigen is displayed on the surface of antigen-presenting cells, usually dendritic cells in peripheral lymphoid organs. T cells require antigen-presenting cells for activation because the form of antigen they recognize is different from that recognized by B cells. Whereas B cells recognize intact protein antigens, for example, T cells recognize fragments of protein antigens that have been partly degraded inside the antigen-presenting cell. Special proteins, called MHC proteins, bind to the peptide fragments and carry them to the surface of the antigen-presenting cell, where T cells can recognize them. The second difference is that, once activated, effector T cells act only at short range, either within a secondary lymphoid organ or after they have migrated into a site of infection. Effector B cells, by contrast, secrete antibodies that can act far away. Effector T cells interact directly with another host cell in the body, which they either kill (as in the case of an infected host cell, for example) or signal in some way (as in the case of a B cell or macrophage, for example). We shall refer to such host cells as target cells. However, because these traget cells must display an antigen bound to an MHC protein on their surface for a T cell to recognize them, they are also antigen-presenting cells. There are three main classes of T cells - cytotoxic T cells, helper T cells, and regulatory (suppressor) T cells. Effector cytotoxic T cells directly kill cells that are infected with a virus or some other intracellular pathogen. Effector helper T cellshelp stimulate the responses of other cells - mainly macrophages, dendritic cells, B cells, and cytotoxic T cells. Effector regulatory T cells suppress the activity of other cells, especially of self-reactive effector T cells.
SLIDE 42 T cell receptors (TCRs) are antibody-like heterodimers Because T cell responses depend on direct contact with an antigen-presenting cell or a target cell, T cell receptors (TCRs), unlike antibodies made by B cells, exist only in membrane-bound form and are not secreted. TCRs resemble antibodies. They are composed of two disulfide-linked polypeptide chains, each of which contains two Ig-like domains, one variable and one constant. Moreover, the threedimensional structure of the extracellular part of a TCR looks very much like one arm of a Y-shaped antibody molecule. On most T cells, the TCRs have one a chain and one b chain. The genetic loci that encode the a and b chains are located on different chromosomes. Like an antibody heavy-chain locus, the TCR loci contain separate V, D, and J gene segments (or just V and J gene segments in the case of the a chain locus), which are brought together by site-specific recombination during T cell development in the thymus. With one exception, T cells use the same mechanisms to generate TCR diversity as B cells use to generate antibody diversity. Indeed, they use the same V(D)J recombinase, including the RAG proteins. The mechanism that does not operate in TCR diversification is antigen-driven somatic hypermutation. Thus, the affinity of the receptors tends to be low, although T cells with the highest affinities are preferentially selected by antigen to persist as memory cells. T cells can partly compensate for their low affinity by increased avidity, which results when multiple TCRs bind simultaneously to multiple membrane-bound ligands (the peptide–MHC complexes that we describe later). Moreover, various co-receptors and cell–cell adhesion proteins greatly strengthen the binding of a T cell to an antigen-presenting cell or a target cell. A minority of T cells, instead of making a and b chains, make a different but related type of receptor heterodimer, composed of g chains and d chains. Although these cells normally make up 5–10% of the T cells in human blood, they can be the dominant T cell population in epithelia (in the skin and gut, for example). The functions of these cells are less well understood than those of T cells expressing a/b TCRs. As with antigen receptors on B cells, the TCRs are tightly associated in the plasma membrane with a number of invariant membrane-bound proteins that are involved in passing the signal from an antigen-activated receptor to the cell interior.
SLIDE 43 Antigen presentation by dendritic cells can either activate or tolerize T cells Naïve cytotoxic or helper T cells must be activated to proliferate and differentiate into effector cells before they can kill or help their target cells, respectively. This activation occurs in peripheral lymphoid organs on the surface of activated dendritic cells that display foreign antigen complexed with MHC proteins on their surface, along with co-stimulatory proteins. By contrast, memory T cells can be activated by other types of antigen-presenting cells, including macrophages and B cells, as well as by dendritic cells. Various kinds of dendritic cells interact with T cells, but they all have a single known function, which is to present antigens that either activate or suppress the T cells. Dendritic cells are located in tissues throughout the body, including the central and peripheral lymphoid organs. Wherever they encounter invading microbes, they endocytose the pathogens or their products. If the encounter is not in a lymphoid organ, the dendritic cells carry the foreign antigens via the lymph to local lymph nodes or gut-associated lymphoid organs. The encounter with a pathogen activates pattern recognition receptors of the dendritic cell, which is thereby induced to mature from an antigen-capturing cell to an activated antigen-presenting cell that can activate T cells. Dendritic cells have to be activated in order to activate naïve T cells, and they can also be activated by tissue injury or by effector helper T cells. Tissue injury is thought to activate dendritic cells by the release of heat shock proteins and uric acid crystals when cells die by necrosis rather than by apoptosis. Activated dendritic cells display three types of protein molecules on their surface that have a role in activating a T cell to become an effector cell or a memory cell: (1) MHC proteins, which present foreign antigen to the TCR, (2) co-stimulatory proteins, which bind to complementary receptors on the T cell surface, and (3) cell–cell adhesion molecules, which enable a T cell to bind to the antigen-presenting cell for long enough to become activated, which is usually hours. In addition, activated dendritic cells secrete a variety of cytokines that can influence the type of effector helper T cell that develops, as well as where the T cell migrates after it has been stimulated. T cells activated by dendritic cells isolated from gut-associated Peyer’s patches, for example, but not by those isolated from lymph nodes, migrate to the small intestine where their antigens are likely to be located. Nonactivated dendritic cells also have important roles. They help induce self-reactive T cells to become tolerant, both in the thymus and in other organs; such dendritic cells present self antigens in the absence of the co-stimulatory molecules required to activate naïve T cells. They induce tolerance in at least two ways: they can stimulate abortive responses in the T cell that lead to either inactivation or apoptosis, and they can activate regulatory T cells to suppress the activity of another T cell.
SLIDE 44 Effector cytotoxic T cells induce infected target cells to kill themselves Cytotoxic T cells protect vertebrates against intracellular pathogens such as viruses and some bacteria and parasites that multiply in the host-cell cytoplasm, where they are sheltered from antibody-mediated attack. Cytotoxic T cells do this by killing the infected cell before the microbes can proliferate and escape from the infected cell to infect neighboring cells. The intracellular microbes can be recognized by T cells because vertebrate cells have mechanisms for displaying fragments of their intracellular proteins on the cell surface, where they are bound to MHC proteins. Once a cytotoxic T cell has been activated by an infected antigen-presenting cell to become an effector cell, it can kill any target cell harboring the same pathogen. Using its TCR, the effector cytotoxic T cell first recognizes a microbial antigen bound to an MHC protein on the surface of an infected target cell. This causes the T cell to reorganize its cytoskeleton and focus its killing apparatus on the target. Focus is achieved when the TCRs actively aggregate—along with various co-receptors, adhesion molecules, and signaling proteins—at the T cell/target cell interface, forming an immunological synapse. A similar synapse forms when an effector helper T cell interacts with its target cell. In this way, effector T cells avoid delivering their signals to neighboring cells. Once bound to its target cell, an effector cytotoxic T cell can employ one of two strategies to kill the target, both of which operate by inducing the target cell to kill itself by undergoing apoptosis. In killing an infected target cell, the cytotoxic T cell usually releases a pore-forming protein called perforin, which is homologous to the complement component C9. The cytotoxic T cell stores perforin in secretory vesicles and releases it by local exocytosis at the point of contact with the target cell. Perforin then polymerizes in the target cell plasma membrane to form transmembrane channels. The secretory vesicles also contain serine proteases, which are thought to enter the target cell cytosol through the perforin channels. One of the proteases, called granzyme B, activates a pro-apoptotic Bcl2 protein called Bid by producing a truncated form of the protein called tBid; tBid then releases cytochrome c from mitochondria, triggering a proteolytic caspase cascade that kills the cell by apoptosis. Mice with an inactivated perforin gene cannot generate pathogen-specific cytotoxic T cells, and they show an increased susceptibility to certain viral and intracellular bacterial infections. In the second killing strategy, the cytotoxic T cell activates a death-inducing caspase cascade in the target cell less directly. A homotrimeric protein on the cytotoxic T cell surface called Fas ligand binds to transmembrane receptor proteins on the target cell called Fas. The binding alters the Fas proteins so that their clustered cytosolic tails recruit procaspase-8 into a complex via an adaptor protein. The recruited procaspase-8 molecules thereby become activated and initiate a caspase cascade that leads to apoptosis.
SLIDE 45 Effector helper T cells help activate other cells of the innate and adaptive immune systems In contrast to cytotoxic T cells, helper T cells are crucial for defense against both extracellular and intracellular pathogens. They help stimulate B cells to make antibodies that help inactivate or eliminate extracellular pathogens and their toxic products. They also activate macrophages to destroy any intracellular pathogens multiplying within the macrophage’s phagosomes, and they help activate cytotoxic T cells to kill infected target cells. They can also stimulate a dendritic cell to maintain it in an activated state. Once an antigen-presenting cell activates a helper T cell to become an effector cell, the helper cell can then help activate other cells. It does this both by secreting a variety of co-stimulatory cytokines and by displaying co-stimulatory proteins on its surface. When activated by its binding to an antigen on a dendritic cell, a naïve helper T cell usually differentiates into either of two distinct types of effector helper cell, called TH1 and TH2. TH1 cells are mainly involved in immunity to intracellular microbes and help activate macrophages, cytotoxic T cells, and B cells. TH2 cells are mainly involved in immunity to extracellular pathogens, especially multicellular parasites, and they help activate B cells to make antibodies against the pathogen. The nature of the invading pathogen and the types of innate immune responses it elicits largely determine which type of helper T cell develops. This, in turn, determines the nature of the adaptive immune responses mobilized to fight the invaders. In some cases, a naïve helper T cell that encounters its antigen in a peripheral lymphoid organ develops into an effector cell that suppresses rather than helps an immune response. Such regulatory T cells, however, mostly develop in the thymus, as a distinct class of T cell.
Regulatory T Cells Suppress the Activity of Other T Cells Regulatory T cells were originally identified by their ability to suppress the activity of other lymphocytes, such as effector helper and cytotoxic T cells and of dendritic cells. Although they make up less than 10% of the T cells in the blood and peripheral lymphoid organs, regulatory T cells play a crucial part in immunological self tolerance by suppressing the activity of self-reactive effector helper and cytotoxic T cells. They also help prevent excessive T cell responses to microbial antigens in chronic infections. In both these ways, they help prevent adaptive immune responses from damaging host tissues. A breakthrough in understanding regulatory T cells was the discovery that they alone express the transcription factor Foxp3, which serves as both an unambiguous marker of these cells and a master controller of their development. When the gene encoding this protein is inactivated in mice or humans, for example, the individuals specifically fail to produce regulatory T cells and develop an early and fatal autoimmune disease involving multiple organs. It is still uncertain how regulatory T cells suppress the action of other lymphocytes.
SLIDE 46 T Cells recognize foreign peptides bound to MHC proteins

Both cytotoxic T cells and helper T cells are initially activated in peripheral lymphoid organs by recognizing foreign antigen on the surface of an antigen-presenting cell, which is a dendritic cell in the case of a naïve T cell. The antigen is usually in the form of peptide fragments that are generated by the degradation of foreign protein antigens inside the antigen-presenting cell. The recognition process depends on the presence of MHC proteins in the antigen-presenting cell. These bind fragments, carry them to the cell surface, and present them there—along with co-stimulatory signals - to the T cells. Once activated, effector T cells then recognize the same peptide–MHC complex on the surface of the target cell they influence, which may be a B cell, a cytotoxic T cell, or an infected macrophage in the case of a helper T cell, or any infected host cell in the case of a cytotoxic T cell; for helper T cells, it may also be the dendritic cell itself. A large complex of genes called the major histocompatibility complex (MHC) encodes MHC proteins. There are two main classes of MHC proteins, and they are both structurally and functionally distinct. Class I MHC proteins mainly present foreign peptides to cytotoxic T cells, and class II MHC proteins mainly present foreign peptides to helper and regulatory T cells. Before examining the mechanisms by which protein antigens are processed for presentation to T cells, we must look more closely at the MHC proteins themselves, which have such a critical role in T cell function.

SLIDE 47 Class I and class II MHC proteins are structurally similar heterodimers Class I and class II MHC proteins have very similar overall structures. They are both transmembrane heterodimers with extracellular N-terminal domains that bind antigen for presentation to T cells. Class I MHC proteins consist of a transmembrane a chain, which is encoded by a class I MHC gene, and a small extracellular protein called b2-microglobulin. The b2-microglobulin does not span the membrane and is encoded by a gene that does not lie in the MHC gene cluster. The a chain is folded into three extracellular globular domains (a1, a2, and a3), and the a3 domain and the b2-microglobulin, which are closest to the membrane, are both similar to an Ig domain. The two N-terminal domains of the a chain, which are farthest from the membrane, contain the polymorphic (variable) amino acids that T cells recognize in transplantation reactions. These domains bind a peptide and present it to cytotoxic T cells. Like class I MHC proteins, class II MHC proteins are heterodimers with two conserved Ig-like domains close to the membrane, and two polymorphic (variable) N-terminal domains farthest from the membrane. In these proteins, however, both chains (a and b) are encoded by genes within the MHC, and both span the membrane. The two polymorphic domains bind a peptide and present it to helper or regulatory T cells. The presence of Ig-like domains in class I and class II proteins suggests that MHC proteins and antibodies have a common evolutionary history. The locations of the genes that encode class I and class II MHC proteins in humans. In addition to the classic class I MHC proteins, there are many class-I-MHClike proteins, which form dimers with b2-microglobulin. These proteins are encoded by genes outside the MHC and are much less polymorphic than MHC proteins, but some of them present specific microbial antigens, including some lipids and glycolipids, to T cells. Although the functions of most of them are unknown, some have a role in brain development.
SLIDE 48 An MHC protein binds a peptide and interacts with a T cell receptor Any individual can make only a small number of different classic MHC proteins, which together must be able to present peptide fragments from almost any foreign protein to T cells. Thus, unlike an antibody molecule, each MHC protein has to be able to bind a very large number of different peptides. X-ray crystallographic analyses of MHC proteins have revealed the structural basis for this versatility. A class I MHC protein has a single peptide-binding site located at one end of the molecule, facing away from the plasma membrane. This site consists of a deep groove between two long a helices; the groove narrows at both ends so that it is only large enough to accommodate an extended peptide about 8–10 amino acids long. In fact, when a class I MHC protein was first analyzed by x-ray crystallography, this groove contained bound peptides that had co-crystallized with the MHC protein, suggesting that once a peptide binds to this site it does not normally dissociate. A typical peptide binds in the groove of a class I MHC protein in an extended conformation, with its terminal amino group bound to invariant amino acids of the MHC protein at one end of the groove and its terminal carboxyl group bound to invariant amino acids at the other end of the groove. Some amino acid side chains of the peptide bind to variable (polymorphic) amino acids of the MHC protein distributed along the groove, while other side chains point outward, in a position to be recognized by TCRs on cytotoxic T cells. Because the invariant amino acids of the MHC protein at the ends of the groove recognize features of the peptide backbone that are common to all peptides, each allelic form of a class I MHC protein can bind a large variety of peptides of diverse sequence. At the same time, the polymorphic MHC amino acids along the groove, which bind specific side chains of the peptide, ensure that each allelic form binds and presents a distinct characteristic set of peptides. Thus, the six types of class I MHC proteins in an individual can present a broad range of foreign peptides to the cytotoxic T cells, but in each individual they do so in slightly different ways. The three-dimensional structure of class II MHC proteins is very similar to that of class I proteins, but the antigen-binding groove does not narrow at the ends, so it can accommodate longer peptides, which are usually 12–20 amino acids long. Moreover, the peptide is not bound at its ends but is instead held by interactions with invariant amino acids of the MHC protein distributed along the length of the groove. As in the case of class I MHC proteins, side chains of other amino acids in the peptide either bind to polymorphic MHC amino acids along the groove or point upward to be recognized by TCRs on helper or regulatory T cells. A class II MHC groove can accommodate a more heterogeneous set of peptides than can a class I MHC groove. Thus, although an individual makes only a small number of types of class II proteins, each with its own unique peptide-binding groove, together these proteins can bind and present an enormous variety of foreign peptides to helper T cells, which have a crucial role in almost all adaptive immune responses. X-ray crystallographic analyses of complexes formed between a soluble TCR and a soluble MHC protein with peptide in its binding groove revealed the way in which the TCR recognizes a peptide-MHC complex. Recombinant DNA technology produced the soluble proteins for these experiments. In each case studied, the TCR fits diagonally across the peptide-binding groove and binds through its Va and Vb hypervariable loops to both the walls of the groove and the peptide. Soluble peptide–MHC complexes are now widely used to detect T cells with a particular specificity; they are usually cross-linked into tetramers so that they can bind to four TCRs on the T cell surface with strong avidity.
SLIDE 49 CD4 and CD8 co-receptors bind to invariant parts of MHC proteins The affinity of TCRs for peptide–MHC complexes on an antigen-presenting cell or target cell is usually too low by itself to mediate a functional interaction between the two cells. T cells normally require accessory receptors to help stabilize the interaction by increasing the overall strength of the cell-cell adhesion. Unlike TCRs or MHC proteins, the accessory receptors do not bind foreign antigens and are invariant. When accessory receptors have a direct role in activating the T cell by generating their own intracellular signals, they are called co-receptors. The most important and best understood of the co-receptors on T cells are the CD4 and CD8 proteins, both of which are single pass transmembrane proteins with extracellular Ig-like domains. Like TCRs, they recognize MHC proteins, but, unlike TCRs, they bind to invariant parts of the protein, far away from the peptide-binding groove. CD4 is expressed on both helper T cells and regulatory T cells and binds to class II MHC proteins, whereas CD8 is expressed on cytotoxic T cells and binds to class I MHC proteins. Thus, CD4 and CD8 contribute to T cell recognition by helping the T cell to focus on particular MHC proteins, and thereby on particular types of target cells: the recognition of class I MHC proteins allows cytotoxic T cells to focus on any host cell, while the recognition of class II MHC proteins allows helper T cells to focus on a small subset of cells-most notably dendritic cells, macrophages, and B cells. The cytoplasmic tail of the CD4 and CD8 proteins is associated with a member of the Src family of cytoplasmic tyrosine kinases called Lck, which phosphorylates various intracellular proteins on tyrosines and thereby participates in the activation of the T cell. Antibodies to CD4 and CD8 are widely used as tools to help distinguish between the main classes of T cells, in both humans and experimental animals: whereas only cytotoxic T cells express CD8, both helper and regulatory T cells express CD4. Ironically, the AIDS virus (HIV) uses CD4 molecules (as well as chemokine receptors) to enter helper T cells. AIDS patients are susceptible to infection by microbes that are not normally dangerous because HIV depletes helper T cells. As a result, most AIDS patients die of infection within several years of the onset of symptoms, unless they are treated with a combination of powerful anti-HIV drugs. HIV also uses CD4 and chemokine receptors to enter macrophages, which also have both of these receptors on their surface. Before a T cell can recognize a foreign protein, the protein has to be processed inside an antigen-presenting cell or target cell so that it can be displayed as peptide-MHC complexes on the cell surface.
SLIDE 50 Cytotoxic T cells respond to fragments of foreign cytosolic proteins in association with class I MHC proteins The cytotoxic T cells of any individual can recognize a specific foreign antigen on a target cell only when the target cell expresses at least some of the allelic forms of class I MHC proteins expressed by that individual, a phenomenon known as MHC restriction. Further, in killing a virus-infected cell, a cytotoxic T cell recognizes degraded fragments of internal proteins of the virus that are bound to class I MHC proteins on the infected cell surface. Because a T cell can recognize tiny amounts of foreign antigen (as few as 1–10 peptide–MHC complexes for T cells with the highest affinity receptors), only a tiny fraction of the fragments generated from viral proteins have to bind to class I MHC proteins and get to the cell surface to trigger an effector cytotoxic T cell to attack. The internal viral proteins are synthesized in the cytosol of the infected cell. Proteolytic degradation in the cytosol is mainly mediated by an ATP- and ubiquitin-dependent mechanism that operates in proteasomes - large proteolytic enzyme complexes constructed from many different protein subunits. All proteasomes are probably able to generate peptide fragments of appropriate length to fit in the groove of class I MHC proteins, as even bacterial proteasomes can do so. This suggests that the MHC groove evolved to fit peptides of around this length. Nonetheless, some proteasomes are apparently specialized for producing peptides for class I MHC proteins, as they contain two subunits that are encoded by genes located within the MHC chromosomal region. How do peptides generated in the cytosol make contact with the peptide-binding groove of class I MHC proteins in the lumen of the endoplasmic reticulum? The answer initially came through observations of mutant cells in which class I MHC proteins are not expressed at the cell surface but are instead degraded within the cell. The mutant genes in these cells proved to encode subunits of a protein belonging to the family of ABC transporters. This transporter is located in the ER membrane and uses the energy of ATP hydrolysis to pump peptides from the cytosol into the ER lumen. The genes encoding its two subunits are located in the MHC chromosomal region, and if either gene is inactivated by mutation, cells are unable to supply peptides to class I MHC proteins. It is striking that the class I MHC proteins in such mutant cells are degraded inside the cell without reaching the cell surface. This occurs because peptide binding is normally required for the proper folding of these proteins: until it binds a peptide, a class I MHC protein remains in the ER, tethered to an ABC transporter by a chaperone protein; without a peptide bound, the trapped MHC proteins in the mutant cells eventually undergo proteolysis. In all cells, peptide fragments come from the cells’ own cytosolic and nuclear proteins that are degraded in the processes of normal protein turnover and quality control mechanisms. (Surprisingly, more than 30% of the proteins made by mammalian cells are apparently faulty and are degraded in proteasomes soon after they are synthesized.) These peptides are constantly being pumped into the ER and are carried to the cell surface by class I MHC proteins. They are not antigenic, however, because the cytotoxic T cells that could recognize them have either been eliminated, inactivated, or suppressed by regulatory T cells in the process of self-tolerance.
SLIDE 51 interferon- (IFN) When an antigen activates cytotoxic T cells or TH1 helper T cells to become effector cells, the effector cells secrete the cytokine IFN, which greatly enhances anti-viral responses. The IFNg acts on virus-infected host cells in two ways. It blocks viral replication, and it increases the expression of many genes within the MHC chromosomal region. These genes include those that encode class I MHC proteins, the two specialized proteasome subunits, and the two subunits of the peptide transporter located in the ER. Thus, the machinery in a host cell that is required for presenting viral antigens to cytotoxic T cells is coordinately called into action by IFNg, creating a positive feedback loop that amplifies the immune response and culminates in the death of the infected cell.
SLIDE 52 Helper T cells respond to fragments of endocytosed foreign protein associated with class II MHC proteins Unlike cytotoxic T cells, helper T cells do not act directly to kill infected cells. Instead, they stimulate macrophages to be more effective in destroying intracellular microorganisms, and they help B cells and cytotoxic T cells to respond to microbial antigens. Like the viral proteins presented to cytotoxic T cells, the proteins presented to helper T cells on dendritic cells or target cells are degraded fragments of foreign proteins. The fragments are bound to class II MHC proteins in much the same way that virus-derived peptides are bound to class I MHC proteins. But both the source of the peptide fragments presented and the route they take to find the MHC proteins generally differ. Rather than being derived from foreign protein synthesized in the cytosol of a cell, the foreign peptides presented to helper T cells are derived from endosomes. Some come from extracellular microbes or their products that the antigenpresenting cell has endocytosed and degraded in the acidic environment of its endosomes. Others come from microbes growing within the endocytic compartment of the antigen-presenting cell. In either case, the peptides do not have to be pumped across a membrane because they are generated in a compartment that is topologically equivalent to the extracellular space. Instead of entering the lumen of the ER, where the class II MHC proteins are synthesized and assembled, they bind to preassembled class II heterodimers in an endosomal compartment. When the peptide binds, the class II MHC protein alters its conformation, trapping the peptide in the binding groove and transferring it to the cell surface for presentation to helper T cells. A newly synthesized class II MHC protein must avoid clogging its binding groove prematurely in the ER lumen with peptides pumped in from the cytosol. A special polypeptide, called the invariant chain, ensures this by associating with newly synthesized class II MHC heterodimers in the ER. Part of its polypeptide chain lies within the peptide-binding groove of the MHC protein, thereby blocking the groove from binding peptides in the lumen of the ER. The invariant chain also directs class II MHC proteins from the trans Golgi network to a late endosomal compartment. Here, proteases cleave the invariant chain, leaving only a short fragment bound in the peptide-binding groove of the MHC protein. This fragment is then released, freeing the MHC protein to bind peptides derived from endocytosed proteins. In this way, the functional differences between class I and class II MHC proteins are ensured—the former mainly presenting molecules that come from the cytosol, the latter mainly presenting molecules that come from the endocytic compartment. This distinction between antigen presentation to cytotoxic T cells and to helper T cells, however, is not absolute. Dendritic cells, for example, need to be able to activate cytotoxic T cells to kill virus-infected cells even when the virus does not infect dendritic cells themselves. To do so, dendritic cells use a process called cross-presentation, which begins when they phagocytose fragments of virus-infected cells. They then actively transport viral proteins out of the phagosome into the cytosol, where they are degraded in proteasomes; resulting fragments of the viral proteins are then transported into the ER lumen, where they load onto assembling class I MHC proteins. Cross-presentation in dendritic cells also operates to activate cytotoxic T cells against tumor antigens of cancer cells and against the MHC proteins of foreign organ grafts. Most of the class I and class II MHC proteins on the surface of a target cell have peptides derived from self proteins in their binding groove. For class I proteins, the fragments mainly derive from degraded cytosolic and nuclear proteins. For class II proteins, they mainly derive from degraded proteins that originate in the plasma membrane or extracellular fluid and are endocytosed. Only a small fraction of the 105 or so class II MHC proteins on the surface of an antigen-presenting cell will have foreign peptides bound to them. This is sufficient, however: even a single copy of such a peptide–MHC complex on a dendritic cell can activate a helper T cell that has a TCR that binds the complex with a high enough affinity.
SLIDE 53 Potentially useful T cells are positively selected in the thymus We have seen that T cells recognize antigen in association with self MHC proteins but not in association with foreign MHC proteins: that is, T cells show MHC restriction. This restriction results from a process of positive selection during T cell development in the thymus. In this process, those immature T cells (thymocytes) that will be capable of recognizing foreign peptides presented by self MHC proteins are selected to survive and mature, while most of the remainder, which would be of no use to the animal, undergo apoptosis. Thus, MHC restriction is an acquired property of the immune system that emerges as T cells develop in the thymus. The most direct way to study the selection process is to follow the fate of a set of developing T cells of known specificity. This can be done by using transgenic mice that express a specific pair of rearranged a and b TCR genes derived from a T cell clone of known antigen and MHC specificity. Such experiments show that the transgenic T cells mature in the thymus and populate the peripheral lymphoid organs only if the transgenic mouse also expresses the same allelic form of MHC protein as is recognized by the transgenic TCR. If the mouse does not express the appropriate MHC protein, the transgenic T cells die in the thymus. Thus, the survival and maturation of a developing T cell depend on a match between its TCR and the MHC proteins expressed in the thymus (which have self peptides derived from the body’s own proteins bound to them). Similar experiments using transgenic mice in which MHC expression is confined to specific cell types in the thymus indicate that it is MHC proteins on epithelial cells in the cortex of the thymus that are responsible for this positive selection. After positively selected T cells leave the thymus, their continued survival as naïve T cells depends on their continual stimulation by self-peptide–MHC complexes (and the cytokine IL7); this stimulation is enough to promote cell survival but not enough to activate the T cells to proliferate or become effector or memory cells. As part of the positive selection process in the thymus, developing T cells that express TCRs recognizing class I MHC proteins are selected to become cytotoxic cells, while T cells that express TCRs recognizing class II MHC proteins are selected to become either helper cells or regulatory cells. Thus, genetically engineered mice that lack cell-surface class I MHC proteins lack cytotoxic T cells specifically, whereas mice that lack class II MHC proteins lack both helper and regulatory T cells specifically. The development of regulatory T cells depends on special groups of epithelial cells in the thymus medulla called Hassall’s corpuscles. The cells that are undergoing positive selection initially express both CD4 and CD8 co-receptors, and these are required for the selection process: without CD4, helper and regulatory T cells fail to develop, and without CD8, cytotoxic T cells fail to develop. Once they develop, cytotoxic T cells lose CD4, and helper and regulatory T cells lose CD8. Positive selection still leaves a large problem to be solved. If developing cytotoxic and helper T cells with receptors that recognize self peptides associated with self MHC proteins were to mature in the thymus and migrate to peripheral lymphoid tissues, they might wreak havoc. A second, negative selection process in the thymus is required to help avoid this potential disaster.
The function of MHC proteins helps explain their polymorphism The role of MHC proteins in binding foreign peptides and presenting them to T cells helps explain the extensive polymorphism of these proteins. In the evolutionary war between pathogens and the adaptive immune system, pathogens tend to change their antigens to avoid associating with MHC proteins. When a pathogen succeeds, it is able to sweep through a population as an epidemic. In such circumstances, the few individuals that produce a new MHC protein that can associate with an antigen of the altered pathogen have a large selective advantage. In addition, individuals with two different alleles at any given MHC locus (heterozygotes) have a better chance of resisting infection than those with identical alleles at the locus, as they have a greater capacity to present peptides from a wide range of pathogens. Thus, this type of selection will tend to promote and maintain a large diversity of MHC proteins in the population. Support for the idea that infectious diseases have been a driving force for MHC polymorphism has come from studies in West Africa. In this region, individuals with a specific MHC allele have a reduced susceptibility to a severe form of malaria. Although the allele is rare elsewhere, it is found in 25% of the West African population where this form of malaria is common. If greater MHC diversity means greater resistance to infection, why do we each have so few MHC genes encoding these molecules? Why have we not evolved strategies for increasing the diversity of MHC proteins—by alternative RNA splicing, for example, or by the genetic recombination mechanisms used to diversify antibodies and TCRs? One reason for the restricted diversity of MHC proteins in an individual may be that each time a new MHC protein is added to the repertoire, the T cells with TCRs that bind strongly to self peptides bound to the new MHC protein must be eliminated to maintain self tolerance. The elimination of these T cells would counteract the advantage of adding the new MHC protein. Thus, the number of MHC proteins we express is thought to represent a balance between the advantages of presenting a wide diversity of foreign peptides to T cells against the disadvantages of severely restricting the T cell repertoire during negative selection in the thymus. Computer modeling studies support this explanation.
Helper T cells are arguably the most important cells in adaptive immunity, as they are required for almost all adaptive immune responses. They help activate B cells to secrete antibodies, and they help macrophages to destroy ingested pathogens. They also help activate cytotoxic T cells to kill infected target cells, at least partly by stimulating dendritic cells to activate naïve cytotoxic cells more efficiently. As dramatically demonstrated in AIDS patients, without helper T cells we cannot even defend ourselves against many microbes that are normally harmless. Helper T cells themselves, however, can function only when activated to become effector cells. Naïve helper cells are activated on the surface of dendritic cells, which become activated during the innate immune responses triggered by an infection. The innate responses, mainly via activated dendritic cells, also dictate what kind of effector cell a helper T cell will develop into, and they thereby determine the nature of the adaptive immune responses elicited.

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