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 substantial tissue damage.
By far the most important layer of defense is the adaptive immune subsystem. Its key features include its ability to act automatically in response to microbial invasion, generate resistance proportional to the threat, and improve with experience.
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 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 adaptive immune responses occur only under appropriate circumstances. If these regulatory pathways fail, disease or death may result.
A series of steps must occur sequentially for either an antibody-mediated or cell-mediated immune response to occur.
The first step involves the capture and processing of foreign antigens. 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 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 microbial invaders, triggering them to respond by mounting immune responses.
There are two major populations of lymphocytes:
B cells: responsible for antibody responses
T cells: responsible for cell-mediated immune responses
Within the population of T lymphocytes, there are four important subpopulations:
T helper type 1 cells, which provide help to other T cells and macrophages and thereby promote cell-mediated immunity
T helper type 2 cells, which provide assistance to B cells for antibody production
T regulatory cells, which regulate these immune responses
Cytotoxic T cells that kill virus-infected or other abnormal cells
Antibody Responses
Antibodies are B-cell antigen receptors that are synthesized in large quantities and secreted into the bloodstream, where they circulate. They 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 divide repeatedly and differentiate into two descendant populations. One population, antibody-producing plasma cells, is the major sources of antibodies. The other B-cell population becomes memory B cells that can persist within an animal for many 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 this microbe leads in turn to the accumulation of more memory cells, resulting in better protection and reducing the chance it will 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 costimulation 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 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 IgE. Each immunoglobulin class plays a different role in the defense of the body.
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 blocks microbial invasion.
IgE is produced locally by plasma cells and then binds with high affinity to tissue mast cells. On the mast cell it serves as a trigger to detect and respond to specific antigens by causing the mast cell to release potent inflammatory 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. It is not present in all mammals.
T-Cell Help in Animals
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 (DCs) 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 major histocompatibility complex (MHC) molecules. Once formed, these antigen-receptor complexes are carried 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 (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; however, 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 and viruses. Cell-mediated responses, in contrast, are directed against intracellular 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 of dendritic cells (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. For example, 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
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 a protein (CD8) they express on their surface. Cytotoxic T cells circulate continuously through the tissues, seeking out abnormal cells to kill.
All nucleated cells produce various 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 passing 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 protein (CD4). 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 inject their targets with enzymes called granzymes that trigger programmed cell death (apoptosis). As a result, cytotoxic T cells kill virus-infected cells but not normal, healthy cells.
Most cytotoxic T cells die once they are no longer needed; however, 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, memory B cells may make small amounts of antibodies against vaccine antigens for many years after vaccination.
Cell-mediated memory is also due to the development of 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 these 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 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 substantial antiviral activity, growth factors that regulate growth and differentiation of various 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 promote immune responses.
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.
Key Points
B cells make antibodies that protect animals against extracellular invaders such as bacteria.
T cells mount a cell-mediated response that protects animals against intracellular invaders such as viruses.
