Adaptive Immunity

Antibodies are protein molecules that serve as B-cell antigen receptors that can be synthesized in large quantities and secreted by the cell into the bloodstream where they circulate. These proteins are produced by B cells and from B cell–derived 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 antigenic molecule. 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 antigen binding, and under suitable circumstances, these B cells divide repeatedly and differentiate into two subpopulations. One subpopulation is composed of antibody-producing plasma cells, which are capable of enormously increased protein synthesis and are the major sources of antibodies. The other subpopulation is composed of B cells that develop into memory B cells and persist in lymphoid tissues 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 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 and virtually guaranteeing that the organism will never be able to cause disease in that animal. This response is the basis of all vaccination programs.

Although simple in concept, B cell responses and antibody production are made more complex by the need to ensure their careful regulation. Thus, a B cell is not usually able to respond to a bound foreign antigen unless it also receives “permission” in the form of a second signal from cells called helper T cells. These T cells in turn can only be activated if they are presented with antigen under carefully controlled circumstances.

As described above, cell-mediated immune responses are required to combat intracellular invaders such as viruses and some intracellular bacteria. The immune system blocks virus infections by killing the cells that they infect. The cells responsible are called effector, or cytotoxic, T cells. Like T cells, effector T cells undergo development and selection within the thymus, so any T cells capable of killing normal healthy cells are eliminated. The surviving T cells are released into the body, where they circulate continuously through the tissues seeking out abnormal cells.

All nucleated cells produce many different proteins when functioning normally. 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. This involves the cell diverting a small sample of each newly formed protein and fragmenting it in 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 cell’s receptors do not engage a protein fragment, nothing happens. If, however, their antigen receptors bind to a foreign antigen fragment in an MHC-protein complex, the T cell will be signaled to kill the offending cell. Like B cells, effector T cells function only if they receive permission from a helper T cell, specifically a Th1 cell. The cytokines from Th1 cells, especially IFN-γ, must be present if an effector T cell is to kill its target.

Effector T cells bind tightly to target cells expressing foreign antigens and then signal them to destroy themselves through apoptosis. The T cells inject their targets with enzymes called granzymes that trigger this process. As a result, effector T cells eliminate virus-infected cells but not normal, healthy cells. Most effector 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 again.

Effector T cells are especially effective at killing target cells that produce foreign antigens. However, some intracellular organisms, especially intracellular bacteria, are best destroyed by other cell-mediated mechanisms. In these cases, IFN-γ from Th1 cells activates M1 macrophages. As a result, bacteria that can survive within normal macrophages are rapidly destroyed by activated macrophages.

The effectiveness of adaptive immunity is largely a result of its ability to recognize antigens 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 may also be 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.

The cells of the adaptive immune system communicate in several 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 small 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.

The adaptive immune system is carefully regulated by several different cell populations. The most important are T_reg cells, which 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. T_reg cells also play a central role in preventing the development of autoimmunity. Another important population of regulatory T cells are called Th17 cells. These cells, so called because they secrete IL-17, regulate the innate immune system and the development of inflammation.