Introduction (Page 1 of 17) CELLULAR IMMUNITY Humoral immunity is mediated by B lymphocytes and the antibodies they secrete, In this topic, we will explore COON Etasrenren tia ABYC B EB ite tye by T lymphocytes. In cellular immunity, certain T cells, called cytotoxic T cells, act like foot soldiers and engage in direct cell-to-cell attacks that destroy the body's own cells when they have become infected or cancerous. Other T cells, called helper T cells, act to orchestrate the Fri rte tn) Ailes Cte OB tc Teh iom ea oce OR OR ON eaten TomGoals (Page 2 of 17) GOALS © Define cytokines and list some of their functions * List the types and subtypes of T lymphocytes * Distinguish between Class I MHC proieins and Class [I MHC proteins in terms of cellular expression and the source of antigen they display. * Describe T cell activation © Describe how cytotoxic T cells kill their target cells © Explain the central role of helper T cells in adaptive immunity. © Describe the role of regulatory T cells | WHAT YOU NEED TO KNOW = ° Key characteristics of adaptive defense mechanis: * Mechanisms internal host defenses phagocytosis. and the role of NK cells © Common features of B and T lymphocytes. Tao see definitions of terms, click the bold red wordsAdaptive Immunity (Page 7 of 11) The adaptive defenses differ from innate defenses in four key ways. Adaptive defenses 1, Are specific—airected against an identified enemy. Click the sergeantPhagocytes: Recognizing the Enemy (Page 8 of 25) Pathogens that enter the body are often rapidly ingested by phagocytes. This process begins when a phagocyte recognizes and binds a pathogen Mannose receptor Phagocytes use special cell membrane receptc such as the mannose receptor and the Toll-l receptors (TLRs), to recognize and bind T 1 molecules that are found on pathogens and no on normal body cells aS i Toll-ike receptor (TLR) y MacrophageNK Cells: Characteristics (Page 11 of 25) Natural Killer (NE) cells are a type of up 10-15% of blood lymphocytes. Let's compare these unusual lymphocytes to B and T cells Click the NK cell. ‘Antimicrobial proteins Natural killer cell apOverview (Page 3 of 18) Shared features of B and T lymphocyte function include: * Specificity of receptors * Diversity of receptors * Regulation of activation. Activation of either B or T cells leads to the formation of a clonal army of defenders, a process called clonal expansion. Click either of the B or T cell soldiers to see clonal expansion.Cytokines (Page 3 of 17) Before exploring T cells in detail, let's consider a set of small proteins called cytokines. Cytokines play a critical role in the function of the immune system. We have already discussed one group of cytokines, the alpha and bela interferons. Click each image to discover some of the actions of cytokines @Cytokines (Page 3 of 17) Before exploring T cells in detail, let's consider a set of small proteins called cytokines. Cytokines play a critical role in the function of the immune system. We have already discussed one group of cytokines, the alpha and bela interferons. * Promote activation of immune cells * Help defend against viruses (cz and fi interferons) * Control differentiation and proliferation of immune cells * Trigger apoptosis * Promote inflammationCytokines (Page 3 of 17) Cytokines area diverse set of chemical messengers that usually act locally, sometimes on the cell that secretes them, more often on cells nearby, and occasionally (via the bloodstream) on cells far Halper ayy, T cell Let’s Look at two specific examples of cytokines that are important for T cells, interleukin-1 and interleukin-2 Macrophages are part of the innate defenses. The innate defenses often mobilize the adaptive defenses by secreting cytokines, particularly interleukin-1. Interleukin-1 acts as a chemical alarm to alert the immune system to the presence ofa pathogen. Clits the macrophage to learn more about interleukin-1. IMacrophage LymphocyteCytokines (Page 3 of 17) Among its many actions, interleukin- | 1. Promotes activation of lymphocytes Helper T cell Click the lymphocyte to activate it LymphocyteCytokines (Page 3 of 17) Among its many actions, interleukin-1 Promotes activation of lymphocytes 2. Acts as a pyrogen at the Het hypothalamus (as do other ans cytokines) Click the brain to see pyrogens act. Macrophage LymphocyteCytokines (Page 3 of 17) Among its many actions, interleukin-1 Promotes activation of lymphocytes Acts as a pyrogen at the hypothalamus (as do other cytokines) Stimulates helper T cells to release interleukin-2 Click the helper T cell to release interleukin-2. Helper T cell Macrophage Via the bloodstrearn: LymphocyteCytokines (Page 3 of 17) Among its many actions, interleukin-1 Promotes activation of lymphocytes Acts as a pyrogen at the hypothalamus (as do other cytokines) Stimulates helper T cells to release interleukin-2 Interleukin-2, released by helper T cells, causes proliferation of activated lymphocytes, called clonal expansion. Interleukin-2 acts on the helper T cell that released it as well as on nearby activated lymphocytes Click Next to go to the next page Macrophage LymphocyteCD4 and CD8 Cells (Page 4 of 17) Lymphocytes that mediate cellular immunity can be divided into two major classes based on the presence of certain cell surface proteins called the CD proteins One clase of lymphocytes has CD4 and the other class has CD8 proteins Click each T cell to see CD4 and CD8 surface proteins T cell receptorCD4 and CD8 Cells (Page 4 of 17) Lymphocytes that mediate cellular immunity can be divided into two major classes based on the presence of certain cell surface proteins called the CD proteins One clase of lymphocytes has CD4 and the other class has CD8 proteins About one-third of all T cells have CD3 markers. The other two-thirds have CD4 markers. Click the most common CD marker. cbs T cell receptor T cell receptorCD4 and CD8 Cells (Page 4 of 17) Just as activated B cells become plasma cells, the metnbers of each class of T cell are destined to become different types of effectors when they are activated * Activated CD8 cells become cytotoxic T cells (Te) that kill other cells that have been invaded or become cancerous, * Activated CD4 cells usually becorne helper T cells (TH), which orchestrate the immune response. Occasionally, CD4 cells become regulatory T cells (TRee), cbs T cell receptor T cell receptor Minority (about 1/3) Majority (about 2/3) Click the cell that will become a cytotoxic T cellCD4 and CD8 Cells (Page 4 of 17) Both CD4 and CD3 are co-receptors that bind to different kinds of MHC proteins. This hinding is required to activate the T cell. CD8 binds to the type of MHC protein called class I MHC protein, and CD4 binds to class IL MHC protein. Click the CD protein that binds to class II MHC proteins cbs T cell receptor T cell receptor Minority (about 1/3) Majority (about 2/3) Most become helper T cells, some become regulatory T cells Become cytotoxic T cellsCD4 and CD8 Cells (Page 4 of 17) The human étnmunodeficiency virus (HIV) that is the cause of AIDS binds specifically to CD4 surface proteins. The virus uses these proteins to gain entry into helper T cells before it destroys them, Clinically, the progress of an HIV infection and the response to AIDS treatments is monitored by counting the number of cells displaying CD4 Drag the virus to the CD molecule that will allow it to enter its target cell. cbs T cell receptor T cell receptor Minority (about 1/3) Majority (about 2/3) Most become helper T cells, some become regulatory T cells Binds MHC class II proteins Become cytotoxic T cells Binds MHC clase 1 proteinsCD4 and CD8 Cells (Page 4 of 17) The human étnmunodeficiency virus (HIV) that is the cause of AIDS binds specifically to CD4 surface proteins. The virus uses these proteins to gain entry into helper T cells before it destroys them, Clinically, the progress of an HIV infection and the response to AIDS treatments is monitored by counting the number of cells displaying CD4 cbs Click Next to go to the next page. T cell receptor Minority (about 1/3) Become cytotoxic T cells Binds MHC clase 1 proteins T cell receptor Majority (about 2/3) Most become helper T cells, some become regulatory T cells Binds MHC class II proteinsMHC Proteins: Introduction (Page 5 of 17) Every body cell has a unique set of proteins on its surface that mark it as belonging to self (one’s own body). One major group of these self-antigens is called the MHC proteins. These proteins cradle antigens for presentation to T cells, Recall that T cells do not recognize free antigens, but do recognize antigens combined with an MHC protein. Click the cell to see its MHC proteins.MHC Proteins: Introduction (Page 5 of 17) MHC stands for major histocompatibility : cotnples. Histocampatibility refers to tissue MHC protein compatibility. MHC proteins determine whether a transplanted tissue or organ will — intigen a, aie be accepted or rejected following transplantation. Before any organ transplant, the donor and recipient’ s MHC protems are matched as closely as possible. There are millions of different combinations of MHC that could be expressed! in an individual, making it unlikely that any two people will have exactly the same set of MHC proteins unless they are identical twins Recipient's cell Click this potential donor’s cell to see if its MHCs match the recipient’ s MHCs. Donor cellMHC Proteins: Introduction (Page 5 of 17) MHC stands for major histocompatibility comple. Histacompatibility refers to tissue compatibility. MHC proteins determine whether a transplanted tissue or organ will — intigen a, aie be accepted or rejected following transplantation. Before any organ transplant, the donor and recipient” s MHC protems are matched as closely as possible. There are millions of different combinations of MHC that could be expressed! in an individual, making it unlikely that any two people will have exactly the same set of MHC proteins unless they are identical twins The closer the match, the less likely that the donor organ will be rejected. Click the donor’s cell again to try to get a better match. { MHC protein Recipient's cell Click Nest to go to thenext page Donor cellMHC Proteins: Class | (Page 6 of 17) Cellular immunity is directed against | intracellular pathogens. Cytotoxic T cells are activated CDS cells that attack our own cells if they have become infected by an intracellular pathogen (often a virus) or if they Class | MHC protein have become cancerous. Cytotoxic T cells circulate through the body, f crawling over cells to examine the self-antigens on their surfaces. A T cell kmows when something is wrong inside a cell because class | MHC proteins é continuously bring pieces of endogenous proteins to the surface of the cell for Cytotoxic T cel 4 inspection. Click the normal cell to see class I MHC bringing samples of its proteins to the surfaceMHC Proteins: Class | (Page 6 of 17) Normal cell proteins are continuously degraded in the cytoplasm. Special transporters bring these protein fragments into the endoplasmic reticulum where they are loaded onto newly synthesized class I MHC proteins Click the normal cell protein to see loading of class | MHC Normal cell protein Class I MHC protein Transport proteinMHC Proteins: Class | (Page 6 of 17) Normal cell proteins are continuously degraded in the cytoplasm. Special transporters bring these protein fragments into the endoplasmic reticulum where they are loaded onto newly synthesized class I MHC proteins Click the loaded class 1 MHC protein to transport it to the surface of the cell. Class I MHC protein Transport proteinMHC Proteins: Class | (Page 6 of 17) The process you just saw happens continuously. ILis a way for the immune system to randomly sample proteins in the cytoplasm, and to display their fragments on the cell’s surface, During their education in the thymus, T cells have been taught to ignore self-antigens on MHC Click the antigenic peptide to see the cytotoxic T cell ignore this self-antigen Transport proteinMHC Proteins: Class | (Page 6 of 17) Drag the virus to the cell below it to infect that cell‘MHC Proteins: Class | (Page 6 of 17) Click the viral protein to see it loaded onto class 1 MHC and transported to the cell surface.‘MHC Proteins: Class | (Page 6 of 17) Click the antigenic peptide to see the cytotoxic T cell recognize this foreign antigen. Antigenic peptide Class I MHC proteinMHC Proteins: Class | (Page 6 of 17)MHC Proteins: Class | (Page 6 of 17) Click Next to go to the next page.MHC Proteins: Class II (Page 7 of 17) Only a few kinds of cells have class 11 MHC proteins. These are the antigen-presenting cells: dendritic cells, macrophages, and B cells, These cells communicate with CD4 cells, which are destined to become, or have already become, helper T cells. The antigens that are presented on class II MHC proteins are exogenous antigens—they originate from outside the cell Let's follow an exogenous antigen on its way to being displayed on a class I] MHC protein. Click the dendritic cell to begin this processMHC Proteins: Class Il (Page 7 of 17) Only a few kinds of cells have class 11 MHC proteins. These are the antigen-presenting cells: dendritic cells, macrophages, and B cells, These cells communicate with CD4 cells, which are destined to become, or have already become, helper T cells. The antigens that are presented on class II MHC proteins are exogenous antigens—they originate from outside the cell Let's follow an exogenous antigen on its way to being displayed on a class I] MHC protein. Exogenous antigens originate outside the antigen-presenting cell, usually as pathogens such as bacteria Drag the bacterium onto the dendritic cell to phagocytose it.‘MHC Proteins: Class II (Page 7 of 17) The phagosome fuses with a lysosome, and the dead bacteria are digested into srnall fragments in the phagolysosome Click the phagosome to fuse it with the lysosome Class I] MHC proteinMHC Proteins: Class II (Page 7 of 17) Class I] MHCs are produced in the rough endoplasmic reticulum and are exported to the plasma membrane. On the way, they fuse with the phagolysosome, allowing the fragmented exogenous antigens to be loaded onto the class II MHC. Click the class 1] MHC to see it being loaded and exported to the cell surface. Class I] MHC proteinMHC Proteins: Summary (Page 8 of 17) Clase I and clase Il MHC Class I MHC Proteins i Class II MHC Proteins |] proteins are structurally distinct molecules, but both display antigens on the surface of a cell. Let's see what you can remember about the differences between MHC | and MHC 11 Displayed by Use these two choices to fill in the first row of the table. All nucleated cells APCs (dendtitie cells, macrophages and B cells)MHC Proteins: Summary (Page 8 of 17) Class I] and class II MHC (Class I MHC Proteins i Class 11 MHC Proteins |] APCs (dendritic cells, macrophages and B cells) proteins are structurally distinct molecules, but both display All nucleated cells antigens on the surface of a cell. Let's see what you can remember about the differences f between MHC I and MHC IL q Recognized by Well done! Now see if you can remember what cell recognizes which class of MHC CD4 cells (helper T cells) CD8 cells (cytotoxic T cells)MHC Proteins: Summary (Page 8 of 17) Class Land class IT MHC Class I MHC Proteins [fl Class II MHC Proteins/] proteins are structurally distinct molecules, but both display All nucleated cells as Eee ape a antigens on the surface ofa cell Let's see what you can remember about the differences between MHC [ and MHC I Endogenous (intracellular | Exogenous (phagocytized pathogens, or proteins, | extracellular pathogens) made by cancer cells) i azMHC Proteins: Summary (Page 8 of 17) Class I and class II MHC proteins are structurally distinct molecules, but both display antigens on the surface of a cell Let’s see what you can Displayed. remember about the differences by between MHC I and MHC IL Thereis one exception to Reeagnized these generalized by “messages.” IL occurs during activation of CD8 cells. We will discuss this exception on the next page. Sours Of foreign antigen, Displayed foreign antigen (Class I MHC Proteins i Class 11 MHC Proteins |] All nucleated cells CD8 cells (cytotoxic T cells) Endogenous (intracellular pathogens, or proteins 4, made by cancer cells) I belong to self, but have ‘beet invaded or become cancerous, Kill me! APCs (dendritic cells, macrophages and B cells) CD4 cells (helper T cells) Exogenous (phagocytized extracellular pathogens) Tbelong to self, but have captured an alien invader. This is what it looks like Help me mount a defense against it.Activation of Naive T Cells (Page 9 of 17) Activation of T cells almost always begins with adendritic cell. Dendritic cells capture: * Extracellular antigens directly by phagocytosis © Intracellular antigens in one of two ways 1, By phagacytizing bits of dead cells 2. By receiving antigenic peptides from abnormal cells through gap junctions Because dendritic cells can express high levels of both MHC I and MHC IL, they are primarily responsible for activating bath CD4 and CDE cells \, Fragments of )) dead infected FPce cates jf Dob Click the cell debris to phagocytize foreign antigens Loose connective tissueActivation of Naive T Cells (Page 9 of 17) Activation of T cells almost always begins with adendritic cell. Dendritic cells capture: * Extracellular antigens directly by phagocytosis © Intracellular antigens in one of two ways 1, By phagacytizing bits of dead cells 2. By receiving antigenic peptides from abnormal cells through gap junctions Because dendritic cells can express high levels of both MHC I and MHC IL, they are primarily responsible for activating bath CD4 and CDE cells When a dendritic cell encounters foreign antigen, the innate immune system signals the dendritic cell to migrate ta secondary Iymphoid organs. There it will present its antigens and activate T cells. As it migrates, the dendritic cell matures, expressing large numbers of MHC class I and II proteins, as well as the co-stimulatory molecules that T cells require to become activated.Activation of Naive T Cells (Page 9 of 17) Class MHC proteins presenit endogenous antigens from the cytosol ofa cell. If they are foreign antigens, this sends the message, “Kil me.” Dendbitic cells are the exception to this rule. They have the unique ability to capture exogenous antigens and present them on both class I and class II MHC proteins. Class | MHC on dendritic cells acts as an activation signal for CD8 cells, not asa signal to Kill the dendritic cell Click the dendritic cell to display the exogenous antigen on class J and II MHC proteins.Activation of Naive T Cells (Page 9 of 17) Class MHC proteins presenit endogenous Class I MHC antigens from the cytosol ofa cell. If they protein are foreign antigens, this sends the message, “Kil me.” Dendbitic cells are the exception 7 to this rule. They have the unique ability to Class [MHC capture exogenous antigens and present them on both class I and class II MHC proteins. Class | MHC on dendritic cells acts as an activation signal for CD8 cells, not asa signal to Kill the dendritic cell protein ‘When dendritic cells enter a lymph node, they migrate to the T cell region in the deep cortex. T cells whose receptors match the antigen presented on the dendritic cell will bind to the dendritic cel Click the dendritic cell to bind T cells to it.Activation of Naive T Cells (Page 9 of 17) Forming the T cell receptor-MHC complex is not enough to activate a T cell. Activation 2 ofa T cell requires a two-step process Naive CD 4 cell 1.7 cell receptors binding to MHC proteins bearing antigens 2. The binding of other co-stimulatory molecules on the antigen-presenting cell This process prevents inappropriate activation of the T cell. Naive CD 8 cell Click a T cell to add the co-stimulatory molecules,Activation of Naive T Cells (Page 9 of 17) Once the T cells are activated, the processes of clonal expansion and differentiation occur (see Topic 4) Co-stimulatory molecule — These processes take place in the presence of the cytokines we have discussed, including interleukin-2, which enables clonal expansion. [ee] : . Click a T cell to generate effector cells.Activation of Naive T Cells (Page 9 of 17) ‘While we have shown CD4 and CD@ cells : Co-stimulatory molecul heing activated sirmuttaneausty, this is not 8 ony melee necessarily the case. Each of these T cell types has different effector functions, which we waill describe in detail shortly. sth Click an effector cell to repeat the animation. A We Click Next ta ga to the next page. [Renaion] Interleukin-2 ‘ Helper T cells Memory CD4 Cytotoxic T cells Memory CD8 (effector CD4 T cells) T cells (effector CD8 T cells) T cellsAnergy (Page 10 of 17) Activation of'a T cell is a two-step process, requiring both the specific MHC-antigen complex and co-stimulatory molecules. MHC protein Let’s compare the response of T cells to antigen presentation with and without co-stimulatory molecules \ Drag the T cell to the dendritic cel with a * co-stimulatory molecule to see if it Co-stimulatory molecule becomes activatedAnergy (Page 10 of 17) Antigen-presenting cells only express co-stimulatory molecules when they have been signaled by the innate defense mechanisms that infection is present. When there is no infection, the antigens on the MHC proteins are likely to be self-antigens Activating T cells in response to self-antigens would bea bad idea. Recall that some self-reactive T cells survive the education process. When these cells react with self-antigen in the absence of co-stimulatory molecules, they are permanently inactivated, a process called anergy.Anergy (Page 10 of 17) Antigen-presenting cells only express co-stimulatory molecules when they have been signaled by the innate defense mechanisms that infection is present. When there is no infection, the antigens on the MHC proteins are likely to be self-antigens Activating T cells in response to self-antigens would bea bad idea. Recall that some self-reactive T cells survive the education process. When these cells react with self-antigen in the absence of co-stimulatory molecules, they are permanently inactivated, a process called anergy. Drag the T cell to the dendtitic cell without co-stimulatory molecules. \. Co-stimulatory moleculeAnergy (Page 10 of 17) Even if at some point in the future this anergic cell encounters a dendritic cell with all the correct MHC-antigen and co-stimulatory molecules, it will remain inactive. Drag the anergic T cell to the dendritic cell with co-stimulatory molecules to see if it becomes activatedAnergy (Page 10 of 17) Even if at some point in the future this anergic cell encounters a dendritic cell with all the correct MHC-antigen and co-stimulatory molecules, it will remain inactive. Px, 3 told | gon, d QuitlCytotoxic T Cell Effector Mechanisms (Page 11 of 17) Activated CD8 cells become effector cells called cytotoxic T cells. Like foot soldiers, cytotoxic T cells roam the body searching for a body cell displaying the MHC-antigen pair that they recognize. When they find this identifier, they kill the cell displaying it by triggering apoptosis. Let’s lookcat this process in detail Sy ce Cytotoxic T cell T cell receptor CD38 a tS Viral antigen Class MHC protein Self-antigenCytotoxic T Cell Effector Mechanisms (Page 11 of 17) Because this is an activated, differentiated effector cell, no co-stimulation is required before the cytotoxic T cell delivers its lethal hit.Cytotoxic T Cell Effector Mechanisms (Page 11 of 17) Because this is an activated, differentiated effector cell, no co-stimulation is required before the cytotoxic T cell delivers its lethal hit. There are two ways a cytotoxic T cell triggers apoptosis, The first way involves the release of pore-forming molecules called perforins and hydeolytic enzymes called granzymes. Both perforins and granzymes are contained in granules released by cytotoxic T cells Whena T cell recognizes its target cell, it > 4) mobilizes its granules to the site of attachment and releases them into the narrow gap between the two cells Click the cytotoxic T cell to release its granules.Cytotoxic T Cell Effector Mechanisms (Page 11 of 17) Se a “The released perforin molecules elongate and insert a : themselves into the membrane of the target cell ae where they group together to form a pore. a *e ‘ Virus infested cellCytotoxic T Cell Effector Mechanisms (Page 11 of 17) ‘The pores formed by the perforins are similar in size and shape to those of the membrane attack complex (MAC) formed by complement. Like the MAC, the pores allow movement of molecules in and out of the cell. Among the molecules that enter the target cell are the granzymes released hy the cytotoxic T cell Cytotoxic T cell Perforin pore ok eta antsCytotoxic T Cell Effector Mechanisms (Page 11 of 17) Once inside the cell, the granzymes activate other enzymes, beginning the pre-programmed process of self-destruction, apoptosis Click a granzyme to trigger apoptosis.Cytotoxic T Cell Effector Mechanisms (Page 11 of 17) This first way of triggering apoptosis using perforins and granzymes is assisted.in many cells by a second mechanism. This mechanism uses a special type of apoptosis-indueing receptor on the surface of these cells to which the cytotoxic T cell can bind, triggering apoptosis Cytotoxic T cells and the na ) cells of innate immunity share these two killing mechanisms. These cells also share the job of immune surveillance, patrolling the body for abnormal cells. They differ in that cytotoxic T cells lock for foreign antigens on MHC, while NK cells look for the absence of MHCs. NK cells are thus able to eliminate abnormal cells that cytotoxic T cells cannot detect,Helper T Cells: Central Role (Page 12 of 17) Helper T cells outnurnber cytotoxic T cells by two to one, and helper T cells are more important to the immune system, Without them, there is essentially no adaptive immune response. Helper T cells are almost always required for activation of both B cells and cytotoxic T cells Helper T cells are critical for the activation of B cells. [iG] Ta recap © AB cell that has captured its specific antigen presents the antigen an class II MHC protein to an already-activated helper T cell © The helper T cell binds and provides the co-stinmlatory signals for fall B cell activation. Click the B cell to activate it.Helper T Cells: Central Role (Page 12 of 17) Helper T cells outnurnber cytotoxic T cells by two to one, and helper T cells are more important to the immune system, Without them, there is essentially no adaptive immune response. Helper T cells are almost always required for activation of both B cells and cytotoxic T cells Helper T cells are critical for the activation of B cells. [iG] To recap * AB cell that has captured its specific antigen presents the antigen on class I] MHC protein to an already-activated helper T cell. © The helper T cell binds and provides the co-stimulatory signals for full B cell activation. © The B cell undergoes clonal expansion and differentiation into antibody-seoreting plasma cells and memory cells Click the helper T cell to see how it helps activate cytotoxic T cells Helper T cellHelper T Cells: Central Role (Page 12 of 17) CD4 cells are more easily activated than CDS cells (which become highly destructive cytotoxic T cells). A mature dendritic cell expresses enough co-stimulatory molecules that Dendritic cell it can activate CD4 cells but not usually enough to activate CDE celle. Click the CD8 cell to see if it will be activated bby the dendritic cell Naive CD 8 cellHelper T Cells: Central Role (Page 12 of 17) CD4 cells are more easily activated than CDS cells (which become highly destructive cytotoxic T cells). A mature dendritic cell expresses enough co-stimulatory molecules that it can activate CD4 cells but not usually enough to activate CDE celle. Mo activation occurred because the CD8 cell's co-stimulatory aaolecule has no counterpart on i Naive CD 8 cell £ Co-stimulatory molecule the dendritic cell to which it can bind, Ifa helper T cell recognizes antigen presented on class II MHC proteins by this dendritic cell, then it can help activate the CD¢ cell Click the helper T cell to bind it to the dendritic cell. f q Helper T cell ——Helper T Cells: Central Role (Page 12 of 17) The helper T cell can help in two ways 1. Itcan stimulate the dendritic cell to express additional co-stitnulatory molecules Helper T cell Click the helper T cell ta signal the dendritic cell, telling it to add co-stimulatory molecules, Co-stimulatory molecule CD 8 cellHelper T Cells: Central Role (Page 12 of 17) The helper T cell can help in two ways 1.It can stimulate the dendritic cell to express additional co-stimulatory molecules 2 It can secrete cytokines, including interleukin-2, that help activate the CD8 cell. Helper T cell Click the helper T cell to release interleukin-2Helper T Cells: Central Role (Page 12 of 17) Helper T cells activate both arms of the adaptive immune response. The importance of helper T _§ cells becomes clear in situations where they are Helper T cell —— deficient, such as in acquired immune deficiency syndrome (AIDS), a disease in which CD4 cells are selectively destroyed. In this disease both cellular and humoral immunity are compromised Click Next to go to the next page, CD 8 cellHelper T Cells: Two Types (Page 13 of 17) Any CD4 cell can differentiate into one of two broadly defined types of helper T cells, depending on the type of threat perceived by the innate immune system. These two classes of cells, called Ty] and Ty2, help the immune system fight Dendritic cell different types of pathogens Click the dendritic cell to begin exploring Ty] cells Tyl cell Ty? cell Primary targets Cytokine that promotes differentiation Naive CD4 cell Cytokine secreted by Ty cell Cells activated.Helper T Cells: Two Types (Page 13 of 17) Intraceltular pathogens Ty] development is triggered by the presence of hard-to-kill bacteria in macrophages and by viral infections Click the bacterium in the macrophage to see which cytokines promote differentiation into Ty] cells Tyl cell Ty? cell Primary| _ Intracelialar targets| _ pathogens \ Cytokine that promotes differentiation Cytokine secreted by Ty cell Cells activated.Helper T Cells: Two Types (Page 13 of 17) Notice that the innate defenses trigger the release of interleukin- 12 (IL-12} as they “sound the alarm” and thereby determine the type of response prawided by the adaptive immune system. Click the Ty] cell to see how it helps. Tyl cell Ty? cell Primary | Intraceltular targets} pathogens Cytokine that] yy ana promotes Aiea differentiation Cytokine secreted by Ty cell Cells activated| Tal cellHelper T Cells: Two Types (Page 13 of 17) Tul cells secrete interferon-y which boosts the ability of macrophages to lull engulfed bacteria Interferon-y also promotes cell-mediated immunity by cytotoxic T cells, Dealing with the intracellular pathogens that trigger Ty] formation is the last step in this negative feedback loop. Click the dendritic cell to begin exploring Ty2 cells Tyl cell Ty? cell Primary | Intraceltular targets| _ pathogens Cytokine that] yy 1) sag promotes Aiea differentiation . Gamma Cytokine secreted by| interferon Ty cell CEN-y) andl others , Macrophages, Cells activated |vtotoxic T cells 0 ane a other afm “# K, ar immunity, = . yalHelper T Cells: Two Types (Page 13 of 17) Ty2 development is triggered by extracellular pathogens. Click an extracellular bacterium to see which cytokines promote the differentiation into Ty2 cells - Extracellular _ pathogens Ty cell Ty? cell Primary] Iivecetivlar | Extracettular targets} pathogens pathogens Cytokine that) 9) 19 and Promotes) “others differentiation . Gamma Cytokine secrated by| interferon Ty cell CEN) andl others , Macrophages, Cells activated | stoxic T cellsHelper T Cells: Two Types (Page 13 of 17) Notice that the innate defenses trigger the release of interleukin-4 (IL-4) as they “sound the alarm” and thereby determine the type of response provided by the adaptive immune system, Click the Ty2 cell ta see how it helps. Primary targets Cytokine that promotes differentiation Cytokine secreted by Ty cell Cells activated. Tyl cell Ty? cell Intracellular | Extraceftular pathogens pathogens 1L-12 and IL-4 and others others Gamma interferon (IEN-y) and others Macrophages, cytotoxic T cells TZ cel ———Helper T Cells: Two Types (Page 13 of 17) TZ cells secrete interleukins-4 and 5 which promote B cell activation and development, and the release of certain classes of antibodies Click the B cell to see the consequences of the T2 response Tyl cell Ty? cell Primary| Iniracsliular ] Extracettular targets} pathogens pathogens ee etes IL-1J and IL-4 and differentiation| =" ee , Gamina Cytok eseare interferon IL-4 and Treen; CEN) others | and others ; Macrophages, Cells activated | stoxic T cells BicHelper T Cells: Two Types (Page 13 of 17) Click either the Tyl or Ty2 cell to repeat its animation. Click Next ta go to the next page oe a other ar immunity, Tyl cell Ty? cell z , & Primary| Intracellular | Extracettular gl S. targets} pathogens pathogens 2 \ - i 3, Cytokine that) 12 and IL-4 and Me tte ees| others others ae differentiation , Gamma { Cyto | eseare interferon IL-4 and Treen| _ CEN-y) others and others Tal call . Macrophages, ron Cells activated) -viotoxic T cells Ty2 cellRegulatory T Cells (Page 14 of 17) Helper T cells help activate effector cells. This activation process contains a number of safety checks, keeping the immune systetn from being activated when it is not required. We will now consider the regulatory T cells, whose main function seems to be ta suppress the activity of self-reactive cells and prevent autoimmune diseases. Four examples are illustrated here Click any disease to learn more about the process of preventing autoinamunity. Hemolytic anemia Graves' disease Type 1 Diabetes mellitus Multiple sclerosisRegulatory T Cells (Page 14 of 17) Unlike the mechanisms of self-tolerance we have seen before that involve clonal deletion, regulatory T cells actively suppress other T cells, How might they do this? Let's briefly review the generation of effector T cells and consider how regulatory T cells can interfere Click the thymusRegulatory T Cells (Page 14 of 17) The creation of effector T cells begins with the recognition of antigens presented by an antigen-presenting cell together with the appropriate co-stimulation. This leads to proliferation and differentiation of the naive T cell. Regulatory T cells mature in the thymus They express CD4. There are at least three major kinds of regulatory T cells. Let's explore ways in which they are believed to work Click the thymus to continue. Dendritic cell Effector T cells Naive T cell ‘day —> MO EDRegulatory T Cells (Page 14 of 1 7) There are really only two ways in which immune cells work—either by direct cell-to-cell contact, of by the release of chemical messengers such as cytokines. Regulatory T cells are thought to do both, Reguiatory T cells Click a regulatory T cell to see inhibition wia cell-to-cell contact. Dendritic cell Effector T cells ‘ ee cell | 7 s _» (siloRegulatory T Cells (Page 14 of 17) Click another regulatory T cell to see inhibition via cytokine release.Regulatory T Cells (Page 14 of 17) The properties of regulatory T cells and their potential use in treating autoimmune diseases and preventing transplant rejection are areas of intense research. Click Next to go to the next page. 2 EY ~eConclusion (Page 15 of 17) We have now completed our discussion of cellular iennmunity. You have undoubtedly gained an appreciation for the breadth and depth of the body’s defense systems. You have studied the body's surface ‘atriers, chemicals and cells of innate defenses, and the humoral and cellular arms of adaptive defenses. Just like the defense systetn of a castle, with its soldiers who defend it, the components of the immune system act together to defend the body against those elements that would do it harm. Click Next to go to the summary.Summary (Page 16 of 17) SUMMARY © Cytokines are small peptides that mediate interactions between immune system cells * CDS cells become cytotoxic T cells; CD4 cells become helper T cells (Tq] or Ty2 } or regulatory T cells * Class 1 MHC proteins, found on all cells, present endogenous antigens to CD8 cells, Class I] MHC proteins, found on antigen-presenting cells, present exogenous antigens to CD4 cells © T cell activation requires antigen presentation by an antigen-presenting cell along with the appropriate co-stimulatory molecules * Cytotosic T cells induce apoptosis of target cells by releasing perforins and granzymes © Helper T cells are required for activation of most B cells and CD8 cells, and release cytokines to direct the immune response, © Regulatory T cells act to suppress setf-reactive T cells, preventing autoimmune diseases Click the quiz button to go to the self quiz