Innate immune responses, although critical to the defense of the body, cannot guarantee protection. They lack the flexibility to respond optimally to a diverse set of microorganisms and they may cause significant tissue damage. A third layer of defense is required that can act automatically in response to microbial invasion, generate resistance proportional to the threat, and improve with experience. These are the key features of the adaptive immune system. Adaptive immune responses are of two major types, antibody (humoral) immunity directed against extracellular invaders and cell-mediated immunity directed against intracellular invaders.
Adaptive immune responses must be very carefully regulated. The immune defenses of the body constitute a potent weapon system whose use must be controlled to minimize collateral damage. As a result, much of the immune system is devoted to the production of regulatory cells and cytokines whose function is to ensure that immune responses only occur under appropriate circumstances. If these regulatory pathways fail, disease or death may result.
The adaptive immune system acts through a series of steps that must occur sequentially for either an antibody-mediated or cell-mediated immune response to occur. The first step involves the capture and processing of antigens (an antigen is a substance that is foreign to the host, such as a piece of a bacterium or a viral protein).Once processed (ie, broken into small peptides), these antigens are transported to cell surfaces, where they can be recognized by lymphocytes carrying receptors for antigens. Each antigen receptor is highly specific, and each lymphocyte expresses only a single form of antigen receptor. Thus, millions of cells have the potential to recognize millions of antigens. To ensure that only foreign antigens trigger adaptive immunity, cells with receptors that bind and respond to normal body "self" antigens are selectively killed early in their development. The surviving lymphocytes are situated within lymphoid organs at sites where they can most effectively encounter antigens on microbial invaders, triggering them to respond by mounting immune responses.
There are two major populations of lymphocytes:
B cells - responsible for antibody responses, effector (or cytotoxic)
T cells - responsible for cell-mediated immune responses
Within the population of T lymphocytes there are subpopulations: helper T cells, whose job it is to provide assistance to B cells for antibody production (these are T helper type 2 cells ) and T helper cells that provide help to other T cells and macrophages by secreting certain cytokines (these are T helper type 1 cells); and T regulatory cells, whose job it is to regulate the immune response.
Antibody Responses
Antibodies are B cell antigen receptors that are synthesized in large quantities and secreted into the bloodstream where they circulate. Antibodies are produced by B cells and plasma cells. Antibodies bind to foreign molecules and mark them for destruction by phagocytic cells or complement-mediated lysis. Plasma cells are differentiated B cells optimized to synthesize and secrete enormous quantities of antibodies. Antibodies are critical to host defense against extracellular invaders such as most bacteria, some blood parasites, and viruses traveling between cells.
B cells originate in the bone marrow and reside in lymphoid tissues such as lymph nodes, bone marrow, Peyer's patches, and the spleen. Each B cell is covered by several thousand identical antigen receptors and can bind and respond to only a single antigen. When a microbe enters the body, it will inevitably encounter B cells that can bind to some of its surface antigens. As a result of this antigen binding, and with appropriate additional stimulation, these B cells will divide repeatedly and differentiate into two descendant populations. One population, antibody-producing plasma cells, are the major sources of antibodies. The other B cell population becomes memory B cells that can persist within an animal for months or years. When an animal encounters an antigen for a second time, these memory B cells respond rapidly, producing large numbers of plasma cells (and yet more memory cells). As a result, the animal mounts a vastly improved antibody response, and the invader is rapidly eliminated. Subsequent exposure to a microbe leads in turn to the accumulation of more memory cells, resulting in better protection, virtually guaranteeing that the organism will never again be able to cause disease in that individual. This response is the basis of all vaccination programs.
Although simple in concept, B cell responses and antibody production must be carefully regulated. Thus, a B cell is not usually able to respond to a bound foreign antigen unless it also receives “co-stimulation” in the form of a signal from helper T cells. These helper T cells in turn can only be activated if they, too, are presented with antigen under carefully controlled circumstances.
Antibodies in Animals
Antibodies are proteins called immunoglobulins. Mammals use five different classes of antibodies: immunoglobulin G (IgG), IgM, IgA, IgE, and IgD. The class of immunoglobulin secreted by B cells and plasma cells depends on their location. Cells located in lymphoid organs within the body secrete IgM and IgG, whereas cells located on mucosal surfaces mainly secrete IgA and/or IgE.
IgG is the most abundant immunoglobulin found in the bloodstream and plays the major role in eliminating organisms that succeed in penetrating deep into the body. IgM is usually confined to the bloodstream because it is a very large molecule with much more antigen binding capacity compared with the smaller IgG, which can easily go into interstitial spaces. IgM is produced early in the antibody response, when its high effectiveness compensates for its low quantity.
IgA is produced by B cells and plasma cells located on mucosal surfaces. As a result, IgA is produced and secreted in large amounts into the upper respiratory tract, the GI tract, tears, sweat, etc. On those surfaces, it complements the physical barriers of the body and prevents microbial invasion. IgE is produced locally by plasma cells and then binds with a very high affinity to tissue mast cells. On the mast cell it serves as a sentinel to detect and respond to specific antigens by causing the mast cell to release granules that contain potent vasoactive mediators. IgE is optimized to control invasion by parasites such as helminths or arthropods. However, it also mediates a rapid acute inflammation in allergic states and can trigger life-threatening anaphylaxis. The function of IgD is unclear, but it is believed to play a role in the response to the normal microbiota.
T Cell Help in Animals
As discussed earlier, antibody responses are regulated by the need to receive prior approval from helper T cells. The helper T cells in turn can only be activated when they bind antigen fragments presented by specialized antigen-presenting cells called dendritic cells.
Dendritic cells are macrophage-like cells whose role is to capture and process foreign antigens. Their name derives from their many long, thin filamentous processes or dendrites that extend through tissues to form an antigen-trapping web. For example, a subpopulation of dendritic cells called Langerhans' cells are found in the dermis, where they trap organisms seeking to enter the body through damaged skin. Dendritic cells capture and phagocytize invading microorganisms. Fragments of these foreign antigens persist within the dendritic cells, where they become attached to receptor molecules called MHC molecules. Once formed, these antigen-receptor complexes move to the dendritic cell surface, where they can be recognized by helper T cells.
The receptors in dendritic cells that present antigen fragments are specialized proteins encoded by genes clustered together in the Major Histocompatibility Complex (MHC) (originally identified as the antigens that cause graft rejection, hence their unusual name). There are many thousands of different MHC molecules expressed within an animal population, but relatively few are expressed in any individual animal. Because they play a critical role in binding antigen fragments and activating T cells, MHC molecules effectively determine whether an individual can respond to a foreign antigen. An individual animal possesses MHC molecules that can bind many, perhaps most, foreign antigens, but not all of them. If an animal lacks MHC molecules that can bind an antigen, it will be unable to respond to that specific antigen.
Like B cells, helper T cells possess specific antigen receptors on their surface that are generated randomly when the cells are first produced. When helper T cells mature within the thymus, any cells with receptors that can bind normal body components are killed. As a result, the surviving T cells can respond only to foreign antigens. The antigen receptors on T cells, like those on B cells, are identical on any single cell. Unlike those on B cells, however, the receptors can recognize antigen only when it is bound to an MHC molecule. Thus, when a dendritic cell presents MHC-associated antigen to T cells, only those T cells with appropriate receptors will bind to the dendritic cell. Once in contact, the cells exchange signals that confirm that the T cell is responding to a correctly processed antigen. After T cells receive all the necessary signals, they secrete cytokines that permit their attached B cells to respond to antigens and allow antibody production to proceed.
Antibodies are produced in response to, and directed against, extracellular bacteria. Cell-mediated responses, in contrast, are directed against viruses and intracellular bacteria. The selection of the appropriate form of the immune response is made at an early stage in the immune response. Thus, there are two populations of dendritic cells that can trap and process antigens. One population (DC1 cells) triggers cell-mediated immunity, whereas the other (DC2 cells) triggers antibody formation. These dendritic cell populations send different messages to T cells because they use different cytokines for signaling; for example, DC1 cells secrete IL-12, whereas DC2 cells secrete IL-1. In turn, these different cytokines stimulate two different helper T cell populations: Th1, which promotes cell-mediated immunity, and Th2, which promotes B cell responses and antibody production. Th1 cells secrete a mixture of cytokines typified by interferon-gamma (IFN-gamma). Th2 cells secrete a mixture of cytokines typified by IL-4. B cells will usually respond optimally to a foreign antigen only if they are stimulated by the presence of IL-4 from Th2 cells.
Cell-mediated Immunity
As described above, cell-mediated immune responses are needed to combat intracellular invaders such as viruses and some bacteria. The immune system combats viral infections simply by killing virus-infected cells. The cells responsible for this killing are called effector or cytotoxic T cells. These are also known as CD8+ cells, based on proteins they express on their surface. Cytotoxic T cells also undergo development and selection within the thymus so that any cells capable of killing normal, healthy cells are eliminated. The surviving cytotoxic T cells are released into the body, where they circulate continuously through the tissues, seeking out abnormal cells to kill.
All nucleated cells produce many different proteins. Virus-infected cells, however, are forced by the virus to produce viral proteins. The body, therefore, requires that all nucleated cells send a sample of their newly synthesized proteins to the cell surface. Thus, the cell diverts a small amount of each new protein into a complex enzyme system called a proteasome. The resulting protein fragments are then attached to MHC molecules and carried to the cell surface, where they are available for inspection by effector T cells. If the T cell's receptors do not bind the complex, then it will be left alone. If, however, their antigen receptors bind to a foreign antigen fragment in an MHC-protein complex, then the T cell will kill the cell it is attached to. Like B cells, cytotoxic T cells only function if they receive costimulation from a helper T cell, specifically a Th1 cell. These cells are also called CD4+ helper T cells based on their surface proteins. The cytokines from Th1 cells, especially IFN-gamma, must be present if a cytotoxic T cell is to kill its target.
Cytotoxic T cells bind tightly to any cells expressing foreign antigens and then signal them to commit suicide through apoptosis. The T cells inject their targets with enzymes called granzymes that trigger this process. As a result, cytotoxic T cells eliminate virus-infected cells but not normal, healthy cells. Most cytotoxic T cells die within a few days once they are no longer needed, but a few survive to become long-lived memory cells that respond rapidly should the animal encounter the virus a second time.
Cytotoxic T cells are especially effective at killing target cells producing foreign antigens. However some intracellular organisms, especially intracellular bacteria, are more effectively destroyed by other cell-mediated mechanisms. In these cases, IFN-gamma from Th1 cells activates M1 macrophages. As a result, bacteria that can survive within normal macrophages are rapidly destroyed by activated macrophages.
Immunologic Memory
The effectiveness of adaptive immunity is largely a result of its ability to recognize invading microbes encountered previously and to mount an enhanced and accelerated response against them. The more an animal encounters an antigen, the greater will be its immune response. Immunologic memory depends on the presence of persistent populations of memory cells that accumulate as an animal ages. These memory cells may be very long-lived or, more likely, turn over very slowly. As a result, animals may make small amounts of antibodies to vaccine antigens for many years after vaccination. Cell-mediated memory is also due to the development of very long-lived populations of memory T cells. The effectiveness of vaccines in inducing long-lasting immunity depends in large part on their ability to induce memory cell populations.
Cytokines
The cells of the adaptive immune system communicate in many ways. They can come into physical contact and exchange signals through receptors within the contact area or immunologic synapse. Examples include the contact between T cells and dendritic cells or between effector T cells and their targets. Immune cells can also signal nearby cells by secreting signaling proteins called cytokines. Several hundred different cytokines have been identified. Signaling cells secrete a mixture of cytokines that then bind to receptors on nearby cells. The target cell receives multiple signals that it must integrate to respond appropriately. Cytokines, acting through their specific receptors, can turn the synthesis of specific proteins on or off. They can cause the target cell to divide or differentiate, and they may trigger apoptosis. With hundreds of different cytokines acting in complex mixtures it is sometimes difficult to predict exactly how a specific target cell will respond. Major families of cytokines include the interleukins that mediate signaling between leukocytes, interferons that mediate interactions between cells and have significant antiviral activity, growth factors that regulate growth and differentiation of many different cell types, and tumor necrosis factors that modulate inflammatory responses.
Regulatory Cells
The adaptive immune system is carefully regulated by several different cell populations. Helper T cells that promote immune responses are described earlier. Other T cells are called regulatory T cells (Treg cells). These secrete a mixture of cytokines that inhibit conventional immune responses. They serve to turn off an immune response once it has completed its task and the invading microorganism is eliminated. Treg cells also play a central role in preventing the development of autoimmunity.
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