The BCR on a given B cell may recognize a specific epitope on a protein antigen, internalize and process the protein, and generate peptides that bind to and are presented on MHC class II molecules to specific CD4+ T cells (Fig. 1). In a T cell–dependent B-cell response to a protein antigen, at least two different epitopes of the protein participate in the process: a surface epitope on the native protein is recognized with high specificity by a B cell, and a linear peptide epitope, which may be in any part of the intact protein, is subsequently released by proteolysis, binds to MHC class II molecules, and is recognized by helper T cells (see Fig. 1). These epitopes have to be present in the same antigen molecule, so both cell types that respond to the antigen can be physically brought together to collaborate. The antibodies that are eventually secreted are specific for conformational determinants of the native antigen because the membrane Ig on B cells binds conformational epitopes of proteins, and the same Ig is secreted by plasma cells derived from those B cells. This feature of B-cell antigen recognition determines the fine specificity of the antibody response and is independent of the fact that helper T cells recognize only linear epitopes of processed peptides. In fact, a single B lymphocyte specific for a native epitope may bind and endocytose a protein and present multiple different peptides complexed with MHC-II molecules to different helper T cells, but the resultant antibody response remains specific for the native protein. The peptides that are presented by the B cell to a helper T cell are the same peptides that initially activated the naive CD4+ T cell when they were presented by DCs in the T-cell zone. The process of antigen presentation and the MHC-II pathway have been discussed in Chapter 6.
Fig1. Antigen presentation on B cells to helper T cells. Protein anti gens recognized by membrane immunoglobulin are endocytosed and processed; peptide fragments are presented in association with major histocompatibility complex (MHC) class II molecules. Helper T cells recognize MHC-peptide complexes on the B cells and then stimulate B-cell responses.
The principles outlined here for T–B cell collaboration help to explain a phenomenon that is known as the hapten-carrier effect. Haptens are small chemicals (like penicillin, for instance) that can be recognized by specific antibodies but are not immunogenic by themselves. If, however, haptens are coupled to proteins, which serve as carriers, the conjugates are able to induce antibody responses against the haptens. Analysis of antibody responses to hapten-carrier conjugates provided among the earliest demonstrations of how B and T lymphocytes cooper ate to generate humoral immune responses. There are three important characteristics of antihapten antibody responses to hapten-protein conjugates. First, such responses require both hapten-specific B cells and protein (carrier)-specific helper T cells. Second, to stimulate a response, the hapten and carrier portions have to be physically linked and cannot be administered separately. Third, the interaction is MHC-II restricted; that is, the helper T cells cooperate only with B lymphocytes that express MHC-II molecules that are identical to those that were involved in the initial activation of naive T cells by dendritic cells. All these features of antibody responses to hapten protein conjugates can be explained by the antigen-presenting function of B lymphocytes. Hapten-specific B cells bind the antigen through the hapten determinant, endocytose the hap ten-carrier conjugate, digest the protein component, and present peptides derived from the carrier protein to carrier-specific helper T lymphocytes (see Fig. 1). Thus, the two cooperating lymphocytes recognize different epitopes of the same antigen. The hapten is responsible for efficient internalization of the carrier protein into the B cell, which explains why hapten and carrier must be physically linked. The requirement for MHC associated antigen presentation for T-cell activation accounts for the MHC restriction of T cell–B cell interactions.
The characteristics of humoral responses elucidated for hap ten-carrier conjugates apply to all protein antigens in which one intrinsic determinant, usually a native conformational determinant, is recognized by B cells (and is therefore analogous to the hapten), and another determinant, in the form of a MHC-II associated linear peptide, is recognized by helper T cells (and is analogous to the carrier that is the source of the peptide). The hapten-carrier effect is the basis for the development of con jugate vaccines against encapsulated bacteria; these vaccines contain carbohydrate epitopes recognized by B cells attached to proteins recognized by T cells, discussed later in this chapter.
The helper T cells that recognize antigen presented by antigen specific B cells then provide signals that activate these B cells, dis cussed next.
