Many nonprotein antigens, such as polysaccharides, lip ids, and nucleic acids, stimulate antibody production in the absence of T-cell help, and these antigens and the responses they elicit are termed thymus independent (TI). These anti body responses differ in several respects from responses to T cell–dependent protein antigens (Table 1). The antibodies that are produced in the absence of T-cell help are generally of low affinity and consist mainly of IgM, with limited class switching.
Table1. Properties of Thymus-Dependent and Thymus-Independent Antigens
Subsets of B Cells That Respond to T-Independent Antigens
The marginal zone and B-1 subsets of B cells are especially important for antibody responses to TI antigens. Whereas responses to T-dependent protein antigens are largely mediated by follicular B cells, other B-cell subsets may be the primary responders to TI antigens (see Fig. 1). Marginal zone B cells are a distinct population of B cells that mainly respond to poly saccharides. After activation, these cells differentiate into short lived plasma cells that produce mainly IgM. B-1 cells respond to TI antigens mainly in the peritoneum and in mucosal sites.
Fig1. Primary and secondary humoral immune responses. In a primary immune response, naive B cells are stimulated by antigen, become activated, and differentiate into antibody-secreting cells that produce antibodies specific for the eliciting antigen. A secondary immune response is elicited when the same antigen stimulates memory B cells, leading to production of greater quantities of specific antibody than are produced in the primary response. Note that the characteristics of secondary antibody responses summarized in the table are typical of T-dependent antibody responses to protein antigens.
T-independent antibody responses are initiated mainly in the spleen, peritoneal cavity, and mucosal sites. Macrophages located in the marginal zones surrounding lymphoid follicles in the spleen are particularly efficient at trapping polysaccharides when these antigens are injected intravenously. TI antigens may persist for prolonged periods on the surfaces of marginal zone macrophages, where they are recognized by specific B cells.
Mechanisms of T-Independent Antibody Responses
Most TI antigens are multivalent, composed of repeated identical antigenic epitopes. Such multivalent antigens may induce maximal cross-linking of the BCR complex on specific B cells, leading to activation without a requirement for cognate T-cell help. The most important TI antigens are polysaccharides, glycolipids, and nucleic acids. All of these types of antigens are capable of inducing the production of specific antibodies in T cell–deficient animals. These antigens cannot be processed and presented in association with MHC molecules, and therefore they cannot be recognized by CD4+ helper T cells. In addition, many polysaccharides activate the complement system by the alternative or lectin pathway, generating C3d, which binds to the antigen and is recognized by CR2, thus augmenting B-cell activation (see Fig. 2). As mentioned earlier, TI responses may also be facilitated by additional signals derived from microbial products that activate TLRs on B cells.
Fig2. Role of complement receptor type 2 (CR2) and Toll-like receptors (TLRs) in B-cell activation. In immune responses to microbes, activation of B cells through the B-cell antigen receptor (BCR) may be enhanced by a complement-coated antigen that can ligate both the BCR and CR2 (A), and also by the simultaneous activation of TLRs on B cells by molecules (pathogen-associated molecular patterns [PAMPs]) derived from the microbe (B). Ig, Immunoglobulin.
Although TI responses typically exhibit little class switching, some T-independent nonprotein antigens do induce the production of Ig classes other than IgM. In humans, the dominant antibody class in response to pneumococcal capsular polysaccharide is IgG2. In mice engineered to lack CD40, IgE and many IgG subclasses are barely detectable in the serum, but levels of IgG3 (which resembles human IgG2) and IgA in the serum are reduced to only about half their normal levels. Cytokines produced by non–T cells may stimulate class switching in T-independent responses. As described earlier, in the absence of T cells, BAFF and APRIL produced by cells of myeloid origin, such as dendritic cells and macrophages, can induce the synthesis of AID in antigen-activated B cells through a receptor of the BAFF receptor family called TACI. This may be further facilitated by the activation of TLRs on these B cells. In addition, cytokines such as TGF-β that help to mediate the IgA switch in B cells are secreted by many non lymphoid cells at mucosal sites and may contribute to the generation of IgA antibodies directed against nonprotein antigens.
Protection Mediated by T-Independent Antibodies
The practical significance of TI antigens is that many bacterial cell wall polysaccharides belong to this category, and humoral immunity is the major mechanism of host defense against infections by such encapsulated bacteria. For this reason, individuals with congenital or acquired deficiencies of humoral immunity are especially susceptible to life-threatening infections with encapsulated bacteria, such as pneumococcus, meningococcus, and Haemophilus.
T-independent antigens also contribute to the generation of natural antibodies, which are present in the circulation of normal individuals and are apparently produced without overt exposure to pathogens. Most natural antibodies are low-affinity anticarbohydrate antibodies, postulated to be produced by peritoneal B-1 cells stimulated by bacteria that colonize the gastro intestinal tract and by marginal zone B cells in the spleen. A large proportion of the natural antibodies in humans and mice are specific for oxidized lipids, including phospholipid head groups, such as lysophosphatidylcholine and phosphorylcholine, which are found on bacterial membranes and on apoptotic cells but are not exposed on the surface of healthy host cells. Some experimental evidence indicates that the natural antibodies specific for these phospholipids provide protection against bacterial infections and facilitate the phagocytosis of apoptotic cells. The anti-ABO blood group antibodies, another example of natural antibodies, recognize certain glycolipids (blood group antigens) expressed on the surface of many cell types, including blood cells. Natural antibodies specific for blood group antigens are important barriers to blood transfusion and transplantation but are not important for host defense and are discussed in Chapter 17.
Despite their inability to specifically activate helper T cells, many polysaccharide vaccines, such as the pneumococcal vaccine, induce quite long-lived protective immunity. Rapid and large secondary responses typical of memory (but without much class switching or affinity maturation) may also occur on secondary exposure to these carbohydrate antigens.
