Despite the structural similarities, the receptors on T cells function differently from those on B cells. The functional difference underlies the different roles played by B and T cells in the immune system. B cells secrete antibodies to antigens in blood and other body fluids, but T cells cannot bind to free-floating antigens. Instead they bind to fragments of foreign proteins that are displayed on the surface of body cells. Thus, once a virus succeeds in infecting a cell, it is removed from the reach of circulating antibodies only to become susceptible to the defense system of the T cell.
But how do fragments of a foreign substance come to be displayed on the surface of a body cell? First, the substance must enter the cell, which can happen through either phagocytosis or infection. Next, the invader is partially digested by the body cell, and one of its fragments is moved to the surface of the cell, where it becomes bound to a cell-surface protein. This cell-surface protein is the product of one of a group of molecules encoded by the genes of the major histocompatibility complex (MHC). In humans MHC proteins were first discovered on leukocytes (white blood cells) and therefore are often referred to as HLA (human leukocyte antigens). (For information on the genetic basis of the HLA, see human genetics.) There are two major types of MHC molecules: class I molecules, which are present on the surfaces of virtually all cells of the body that contain nuclei—that is, most body cells—and class II molecules, which are restricted to the surfaces of most B cells and some T cells, macrophages, and macrophage-like cells.
Two main types of mature T cells— cytotoxic T cells and helper T cells—are known. Some scientists hypothesize the existence of a third type of mature T cell called regulatory T cells. Some T cells recognize class I MHC molecules on the surface of cells; others bind to class II molecules. Cytotoxic T cells destroy body cells that pose a threat to the individual—namely, cancer cells and cells containing harmful microorganisms. Helper T cells do not directly kill other cells but instead help activate other white blood cells (lymphocytes and macrophages), primarily by secreting a variety of cytokines that mediate changes in other cells. The function of regulatory T cells is poorly understood. To carry out their roles, helper T cells recognize foreign antigens in association with class II MHC molecules on the surfaces of macrophages or B cells. Cytotoxic T cells and regulatory T cells generally recognize target cells bearing antigens associated with class I molecules. Because they recognize the same class of MHC molecule, cytotoxic and regulatory T cells are often grouped together; however, populations of both types of cells associated with class II molecules have been reported. Cytotoxic T cells can bind to virtually any cell in the body that has been invaded by a pathogen.
T cells have another receptor, or coreceptor, on their surface that binds to the MHC molecule and provides additional strength to the bond between the T cell and the target cell. Helper T cells display a coreceptor called CD4, which binds to class II MHC molecules, and cytotoxic T cells have on their surfaces the coreceptor CD8, which recognizes class I MHC molecules. These accessory receptors add strength to the bond between the T cell and the target cell.
The T-cell receptor is associated with a group of molecules called the CD3 complex, or simply CD3, which is also necessary for T-cell activation. These molecules are agents that help transduce, or convert, the extracellular binding of the antigen and receptor into internal cellular signals; thus, they are called signal transducers. Similar signal transducing molecules are associated with B-cell receptors.
When T-cell precursors leave the bone marrow on their way to mature in the thymus, they do not yet express receptors for antigens and thus are indifferent to stimulation by them. Within the thymus the T cells multiply many times as they pass through a meshwork of thymus cells. In the course of multiplication they acquire antigen receptors and differentiate into helper or cytotoxic T cells. As mentioned in the previous section, these cell types, similar in appearance, can be distinguished by their function and by the presence of the special surface proteins, CD4 and CD8. Most T cells that multiply in the thymus also die there. This seems wasteful until it is remembered that the random generation of different antigen receptors yields a large proportion of receptors that recognize self antigens—i.e., molecules present on the body’s own constituents—and that mature lymphocytes with such receptors would attack the body’s own tissues.
Most such self-reactive T cells die before they leave the thymus, so that those T cells that do emerge are the ones capable of recognizing foreign antigens. These travel via the blood to the lymphoid tissues, where, if suitably stimulated, they can again multiply and take part in immune reactions. The generation of T cells in the thymus is an ongoing process in young animals. In humans large numbers of T cells are produced before birth, but production gradually slows down during adulthood and is much diminished in old age, by which time the thymus has become small and partly atrophied. Cell-mediated immunity persists throughout life, however, because some of the T cells that have emerged from the thymus continue to divide and function for a very long time.
B-cell precursors are continuously generated in the bone marrow throughout life, but, as with T-cell generation, the rate diminishes with age. Unless they are stimulated to mature, the majority of B cells also die, although those that have matured can survive for a long time in the lymphoid tissues. Consequently, there is a continuous supply of new B cells throughout life. Those with antigen receptors capable of recognizing self antigens tend to be eliminated, though less effectively than are self-reactive T cells. As a result, some self-reactive cells are always present in the B-cell population, along with the majority that recognize foreign antigens. The reason the self-reactive B cells normally do no harm is explained in the following section.
In its lifetime a lymphocyte may or may not come into contact with the antigen it is capable of recognizing, but if it does it can be activated to multiply into a large number of identical cells, called a clone. Each member of the clone carries the same antigen receptor and hence has the same antigen specificity as the original lymphocyte. The process, called clonal selection, is one of the fundamental concepts of immunology.
Two types of cells are produced by clonal selection— effector cells and memory cells. Effector cells are the relatively short-lived activated cells that defend the body in an immune response. Effector B cells are called plasma cells and secrete antibodies, and activated T cells include cytotoxic T cells and helper T cells, which carry out cell-mediated responses.
The production of effector cells in response to first-time exposure to an antigen is called the primary immune response. Memory cells are also produced at this time, but they do not become active at this point. However, if the organism is reexposed to the same antigen that stimulated their formation, the body mounts a second immune response that is led by these long-lasting memory cells, which then give rise to another population of identical effector and memory cells. This secondary mechanism is known as immunological memory, and it is responsible for the lifetime immunities to diseases such as measles that arise from childhood exposure to the causative pathogen.
Helper T cells do not directly kill infected cells, as cytotoxic T cells do. Instead they help activate cytotoxic T cells and macrophages to attack infected cells, or they stimulate B cells to secrete antibodies. Helper T cells become activated by interacting with antigen-presenting cells, such as macrophages. Antigen-presenting cells ingest a microbe, partially degrade it, and export fragments of the microbe—i.e., antigens—to the cell surface, where they are presented in association with class II MHC molecules. A receptor on the surface of the helper T cell then binds to the MHC-antigen complex. But this event alone does not activate the helper T cell. Another signal is required, and it is provided in one of two ways: either through stimulation by a cytokine or through a costimulatory reaction between the signaling protein, B7, found on the surface of the antigen-presenting cell, and the receptor protein, CD28, on the surface of the helper T cell. If the first signal and one of the second signals are received, the helper T cell becomes activated to proliferate and to stimulate the appropriate immune cell. If only the first signal is received, the T cell may be rendered anergic—that is, unable to respond to antigen.
A discussion of helper-T-cell activation is complicated by the fact that helper T cells are not a uniform group of cells but rather can be divided into two general subpopulations— TH1 and TH2 cells—that have significantly different chemistry and function. These populations can be distinguished by the cytokines they secrete. TH1 cells primarily produce the cytokines gamma interferon, tumour necrosis factor-beta, and interleukin-2 ( IL-2), while TH2 cells mainly synthesize the interleukins IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13. The main role of the TH1 cells is to stimulate cell-mediated responses (those involving cytotoxic T cells and macrophages), while TH2 cells primarily assist in stimulating B cells to make antibodies.
Once the initial steps of activation have occurred, helper T cells synthesize other proteins, such as signaling proteins and the cell-surface receptors to which the signaling proteins bind. These signaling molecules play a critical role not only in activating the particular helper T cell but also in determining the ultimate functional role and final differentiation state of that cell. For example, the helper T cell produces and displays IL-2 receptors on its surface and also secretes IL-2 molecules, which bind to these receptors and stimulate the helper T cell to grow and divide.
The overall result of helper-T-cell activation is an increase in the number of helper T cells that recognize a specific foreign antigen, and several T-cell cytokines are produced. The cytokines have other consequences, one of which is that IL-2 allows cytotoxic or regulatory T cells that recognize the same antigen to become activated and to multiply. Cytotoxic T cells, in turn, can attack and kill other cells that express the foreign antigen in association with class I MHC molecules, which—as explained above—are present on almost all cells. So, for example, cytotoxic T cells can attack target cells that express antigens made by viruses or bacteria growing within them. Regulatory T cells may be similar to cytotoxic T cells, but they are detected by their ability to suppress the action of B cells or even of helper T cells (perhaps by killing them). Regulatory T cells thus act to damp down the immune response and can sometimes predominate so as to suppress it completely.