Linked recognition relies on the concentration of the appropriate peptide for presentation by MHC class II molecules on the B-cell surface. B cells whose B-cell receptor binds a particular antigen are 10,000 times more efficient at displaying peptide fragments of that antigen on their MHC class II molecules than are B cells that process the antigen through macropinocytosis alone. Linked recognition was originally discovered through studies of the production of antibodies against haptens, which are small chemical groups that cannot elicit antibody responses on their own (see Appendix I, Section A-1). But haptens that are coupled to a carrier protein become immunogenic—known as the hapten carrier effect—for two reasons. The protein can carry multiple hapten groups, allowing it to cross-link B-cell receptors. Also, T cells that are activated against peptides of the carrier protein can become TFH cells and strengthen the antibody response to the hapten. Accidental coupling of a hapten to a protein is responsible for the allergic responses shown by many people to the antibiotic penicillin, which reacts with host proteins to form a coupled hapten that can stimulate an antibody response, as we will learn in Chapter 14.
Linked recognition works to preserve self-tolerance, since autoreactive antibodies will arise only if self-reactive TFH and self-reactive B cells are present at the same time. This is discussed further in Chapter 15. Vaccine design can take advantage of linked recognition, as in the vaccine used to immunize infants against Haemophilus influenzae type b (see Section 16-26).
10-3 B cells that encounter their antigens migrate toward the lymphoid tissues.
The frequency of naive lymphocytes specific for a particular antigen is extremely low (less than 1 in 10,000). Thus, the chance of a random encounter between a T and a B cell with the same antigen specificity should be less than 1 in 108, making it remarkable that B cells ever interact with TFH cells with similar antigen specificity. For these reasons, linked recognition requires a precise regulation of the migration of activated B and T cells—orchestrated by several sets of ligands and receptors—into specific locations within the lymphoid tissues, which serves to increase the chances of a productive interaction (Fig. 10.5).
Naive T cells and B cells express the sphingosine 1-phosphate receptor, S1PR1, which they use to egress from the peripheral lymphoid tissues (see Section 9-7). However, before they exit, they are retained and initially occupy two distinct zones, the T-cell areas and the primary lymphoid follicles (or B-cell areas or B-cell zones), respectively (see Figs 1.18–1.20). These zones are established by different patterns of chemokine receptor expression and chemokine production. Naive T cells express the chemokine receptor CCR7, and localize to zones where its ligands, CCL19 and CCL21, are highly expressed by stromal cells and dendritic cells (see Section 9-3). Circulating naive B cells express CXCR5, and when they migrate into lymphoid tissues, they enter the primary lymphoid follicles, where the chemokine CXCL13 is abundant. Within the follicle, stromal cells and a specialized cell type, the follicular dendritic cell (FDC), secrete CXCL13. The FDC is a nonphagocytic cell of nonhematopoietic origin that bears numerous long processes; it functions by trapping antigen using complement receptors on its cell surface for access by B cells in the follicle.
Once in the follicle, naive B cells encounter the soluble TNF-family cytokine BAFF (see Section 8-8), which is secreted by FDCs, stromal cells, and dendritic cells and which acts as a survival factor for B cells. BAFF can act through three