The activation of B cells results in their proliferation and their eventual differentiation into antibody-secreting plasma cells and memory cells (Fig. 1). Humoral immune responses are initiated in secondary lymphoid organs when antigens interact with antigen-specific naive B cells. Antigens bind to membrane immunoglobulin (Ig)M and IgD on these naive B cells, which function as B-cell antigen receptors to generate signals that initiate the proliferation and differentiation of these cells. Antigen receptors also internalize protein antigens for processing and presentation to helper T cells. The antibody that is secreted by a plasma cell has the same specificity as the original antibody that served as the antigen receptor on the surface of the naive B cell. A single B cell may, within a week, give rise to as many as 5000 plasma cells, each of which can secrete about 2000 antibody molecules every second. This large expansion of cells and the remarkable rate of antibody secretion are needed to keep pace with rapidly dividing microbes.
Fig1. Phases of the humoral immune response. The activation of B cells is initiated by specific recognition of antigens by the surface immunoglobulin (Ig) receptors of the cells. Antigen and other stimuli, including helper T cells, stimulate the proliferation and differentiation of the specific B-cell clone. Progeny of the clone may differentiate into plasma cells that produce IgM or other Ig classes (e.g., IgG), may undergo affinity maturation, or may persist as memory cells (that have also typically undergone class switching and affinity maturation).
Antibody responses are T-dependent or T-independent, depending on the nature of the antigen and the involvement of helper T cells (Fig. 2). Most responses to protein antigens require T-cell help, so these antigens are called T-dependent. The term helper T lymphocyte came from the realization that T cells stimulate, or help, B lymphocytes to produce antibodies. In T-dependent responses, some activated B cells begin to produce antibodies other than IgM; this process is called heavy-chain class (isotype) switching (see Fig. 1). As the response devel ops, activated B cells produce antibodies that bind to antigens with increasing affinity, and these B cells progressively dominate the response; this process is called affinity maturation. In addition to class switching and affinity maturation, helper T cells stimulate the production of long-lived plasma cells and the generation of memory B cells. Multivalent antigens with repeating determinants, such as polysaccharides, can activate B cells without T-cell help. These antigens are called T-independent. T-independent responses are rapid but relatively simple, consisting mostly of low affinity IgM antibodies.
Fig2. T-dependent and T-independent antibody responses. T-dependent antibody responses to protein antigens mainly involve follicular B cells. T-independent responses to multivalent antigens are mediated mainly by marginal zone B cells in the spleen and B-1 cells in mucosal sites. Ig, Immunoglobulin.
Primary and secondary antibody responses to protein anti gens differ qualitatively and quantitatively (Fig. 3). Primary responses result from the activation of previously unstimulated naive B cells, whereas secondary responses are due to the stimulation of expanded clones of memory B cells. Therefore, the secondary response develops more rapidly than does the primary response, and larger amounts of antibodies are produced in the secondary response. Furthermore, because the memory cells have already undergone class switching and affinity maturation, more IgG and IgA are produced compared to IgM, and the affinity of the antibody is higher in secondary responses.
Fig3. 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.
Distinct subsets of B cells respond preferentially to different types of antigens (see Fig. 2). Follicular B cells in secondary lymphoid organs generate most of the antibody responses to protein antigens, and these B-cell responses require collaboration with helper T cells. Like naive T cells, naive follicular B cells express CCR7 and cross high endothelial venules (HEVs) that are in the outer paracortex or T-cell zone of lymph nodes. These B cells express higher levels of CXCR5, which binds the chemokine CXCL13 secreted by stromal cells in lymphoid follicles, including follicular dendritic cells (FDCs). CXCL13 draws the B cells from the vicinity of the HEV that it has emerged from into the follicle. The follicle is the site of initial B-cell recognition of protein anti gens and many of the events in T-dependent antibody responses, as discussed later. Marginal zone B cells in the spleen and other lymphoid tissues and B-1 cells in mucosal tissues and the peritoneum have restricted repertoires that mainly recognize multivalent antigens, such as polysaccharides from blood-borne and ingested or inhaled microbes, and mount primarily T-independent anti body responses. These preferences are not absolute. Some marginal zone B cells participate in T-dependent responses, and some follicular B cells may make T-independent responses.
With this background, we proceed to a discussion of B-cell activation, starting with the interaction of antigen with B cells. We will then describe the role of helper T cells in B-cell responses to protein antigens and the mechanisms of class switching and affinity maturation. We conclude with a discussion of T-independent antibody responses.
