T-DEPENDENT AND T-INDEPENDENT ANTIGENS
The studies with hapten-carrier complexes were followed by many others in which inbred rodents were sublethally irradiated to render them immunoincompetent, and their immune systems were then reconstituted with T lymphocytes, B lymphocytes, or mixtures of T and B lymphocytes obtained from normal animals of the same strain. After reconstitution of the immune system, the animals were challenged with a variety of antigens, and their antibody responses were measured.
For most antigens, including complex proteins, heterologous cells, and viruses, a measurable antibody response was only observed in animals reconstituted with mixtures of T and B lymphocytes. In other words, for most antigens, proper differentiation of antibody-producing cells required T cell “help.” The antigens that could not induce immune re- sponses in T-cell–deficient animals were designated as T-dependent antigens. Structurally, T-dependent antigens are usually complex proteins with large numbers of different, non-repetitive, antigenic determinants.
Other antigens, particularly polysaccharides, can induce antibody synthesis in ani-mals depleted of T lymphocytes and are known as T-independent antigens. It should be noted that in many species there may be a continuous gradation of antigenic responses from T dependence to T independence, rather than two discrete groups of antigens. However, this differentiation is useful as a working classification.
The basic fact that explains the inability of polysaccharides to behave as T-dependent anti-gens is the fact that these compounds do not bind to MHC II molecules and, therefore, can-not be presented to T cells. Immune responses elicited by T-independent antigens are me-diated by different mechanisms that bypass the need for T-cell help.
Some T-independent antigens, such as bacterial lipopolysaccharides (LPS), are mi-togenic and can deliver dual signals to B cells: one by occupancy of the antigen-specific re-ceptor (membrane immunoglobulin) and the other through a second, poorly characterized, co-stimulatory B-cell protein. The engagement of these two receptors would be sufficient to stimulate B cells and promote differentiation into antibody-producing cells.
Other T-independent antigens (such as polysaccharides) are not mitogenic but are composed of multiple sugar molecules, allowing extensive cross-linking of membrane im-munoglobulins. Receptor cross-linking delivers strong activating signals that apparently overrides the need for co-stimulatory signals.
The antibody produced in response to stimulation with T-independent antigens is predom-inantly IgM. The switch to other isotype, such as IgG and IgA, production requires the pres-ence of cytokines and other signals (e.g., those delivered by CD40 interacting with CD40L) delivered by locally responding T cells. There is, therefore, little (if any) synthesis of IgG and IgA after exposure to T-independent antigens. These antigens also fail to elicit im-munological memory, also dependent on the simultaneous activation of T cells, as demon-strated with the hapten-carrier experiments.
The use of polysaccharides as immunogens for immunoprophylaxis has always been unsatisfactory. A decade ago it was discovered that poorly immunogenic polysaccharides induce the same type of immune responses associated with T-dependent immunogens when conjugated to immunogenic proteins. These vaccines act, essentially, as hapten-carrier complexes, in which the polysaccharide plays the role of the hapten, and they are extremely effective .