B-cell activation by many antigens requires both binding of the antigen by the B-cell surface immunoglobulin—the B-cell receptor—and interaction of the B cell with antigen-specific helper T cells. Helper T cells recognize peptide fragments derived from the antigen internalized by the B cells and displayed by the B cells as peptide:MHC class II complexes. Follicular helper T cells stimulate B cells by conjugation in germinal centers, with binding of CD40 ligand on the T cell to CD40 on the B cell, and by their release of cytokines, such as IL-21. Activated B cells also express molecules, such as ICOSL, that can stimulate T cells. The initial interaction between B and T cells occurs at the border of the T-cell and B-cell areas of secondary lymphoid tissue, to which antigen-activated helper T cells and B cells migrate in response to chemokines. Further interactions between T cells and B cells continue after migration into the follicle and the formation of a germinal center.
Fig. 10.26 Properties of different classes of antigen that elicit antibody responses. Some data indicate a minor role for T cells in antibody responses to TI-2 antigens; robust responses to TI-2 antigens can be observed in T-cell-deficient mice.
T cells induce a phase of vigorous B-cell proliferation in the germinal center reaction and direct the differentiation of clonally expanded B cells into either antibody-secreting plasma cells or memory B cells. Immunoglobulin genes expressed in B cells are diversified in the germinal center reaction by somatic hypermutation and class switching, initiated by activation-induced cytidine deaminase (AID). Unlike V(D)J recombination, these processes occur only in B cells. Somatic hypermutation diversifies the V region through the introduction of point mutations that are selected for providing greater affinity for the antigen as the immune response proceeds. Class switching does not affect the V region but increases the functional diversity of immunoglobulins by replacing the Cμ region in the immunoglobulin gene, which is first expressed with another heavy-chain C region to produce IgG, IgA, or IgE antibodies. Class switching provides antibodies with the same antigen specificity but distinct effector capacities. The switching to different antibody isotypes is regulated by cytokines released from helper T cells. Some nonprotein antigens stimulate B cells in the absence of linked recognition by peptide-specific helper T cells. Responses to these thymus-independent antigens are accompanied by only limited class switching and do not induce memory B cells. However, such responses have a crucial role in host defense against pathogens whose surface antigens cannot elicit peptide-specific T-cell responses.
The distributions and functions of immunoglobulin classes.
Extracellular pathogens can invade most sites within the body, and so antibodies must be equally widely distributed to combat them. Most classes of antibodies are distributed by diffusion from their site of synthesis, but specialized transport mechanisms are required to deliver antibodies across the epithelial surfaces lining the mucosa of organs such as the lungs and intestine. The particular heavy-chain isotype of the antibody can either limit antibody diffusion or engage specific transporters that deliver the antibody across epithelia. This part of the chapter describes these mechanisms and the antibody classes that use them to enter compartments of the body where their particular effector functions are appropriate. Here we restrict our discussion to the protective functions of antibodies that result solely from their binding to pathogens, and in the next part of the chapter, we discuss the effector cells and molecules that are specifically engaged by different antibody classes.
10-15 Antibodies of different classes operate in distinct places and have distinct effector functions.