Fig. 10.2 A second signal is required for B-cell activation by either thymus-dependent or thymus-independent antigens. The first signal (indicated as 1) required for B-cell activation is delivered through its antigen receptor (BCR) and activates several pathways as described in Chapter 7. Signaling by the BCR is enhanced by the co-receptors CD21 and CD19, which interact with C3b on opsonized microbial surfaces. For thymus-dependent antigens (first panel), a second signal (indicated as 2) is delivered by a helper T cell (TFH) that recognizes degraded fragments of the antigen as peptides bound to MHC class II molecules on the B-cell surface. CD40L on the TFH cell binds to CD40 on the B cell, activating the non-canonical NFκB signaling pathway via NFκB-inducing kinase (NIK). This induces expression of pro-survival genes such as Bcl-2 (see Section 7-17). For thymus-independent antigens (second panel), a second signal can be delivered through Toll-like receptors that recognize antigen-associated TLR ligands, such as bacterial lipopolysaccharide (LPS) or bacterial DNA, as described in Chapter 3.
B-cell activation by antigen and helper T cells.
The surface immunoglobulin that serves as the B-cell receptor (BCR) plays two roles in B-cell activation in response to pathogens. Like the antigen receptor on T cells, the BCR initiates a signaling cascade upon binding antigens derived from the microbe. In addition, the BCR can deliver the antigen to intracellular sites for antigen processing, so that antigenic peptides bound to MHC class II molecules can be returned to the B-cell surface. These peptide:MHC class II complexes are recognized by antigen-specific helper T cells that have already differentiated in response to the same pathogen. The effector T cells express surface molecules and cytokines that help the B cell to proliferate and to differentiate into antibody-secreting cells and into memory B cells, and a structure called the germinal center (see Section 10-6) is formed during an intermediate phase of the antibody response, before the emergence of longterm plasma cells that generate antibody or of memory B cells. Some microbial antigens can activate B cells directly in the absence of T-cell help, and the ability of B cells to respond directly to these antigens provides a rapid response to many important pathogens. However, the fine tuning of antibody responses to increase the affinity of the antibody for the antigen and the switching to most immunoglobulin classes other than IgM depend on the interaction of antigen-stimulated B cells with helper T cells and other cells in the peripheral lymphoid organs. Thus, antibodies induced by microbial antigens alone tend to have lower affinity and to be less functionally versatile than those induced with T-cell help.
10-1 Activation of B cells by antigen involves signals from the B-cell receptor and either TFH cells or microbial antigens.
As we learned in Chapter 8, activation of naive T cells requires signals derived from the T-cell receptor as well as co-stimulatory signals provided by professional antigen-presenting cells. Similarly, in addition to signals derived from the B-cell receptor, naive B cells also require accessory signals that can arise either from a helper T cell or, in some cases, directly from microbial constituents (Fig. 10.2).
B-cell activation by antigen and helper T cells.