CD40 initiate enzyme cascades that lead to the activation and nuclear translocation of transcription factors, including NF-kB and AP-1, which collectively stimulate B cell proliferation and increased synthesis and secretion of Ig. Similar signaling pathways are activated by TNF receptors (see Chapter 7). CD40-induced transcription factor induction is also crucial for subsequent germinal center formation and for the synthesis of activation-induced deaminase (AID), an enzyme that is required for somatic mutation and isotype switching, as will be discussed later. T cell-mediated dendritic cell and macrophage activation also involves the interaction of CD40L on activated helper T cells with CD40 on dendritic cells and macrophages (see Chapter 10). Thus, this pathway of contact-dependent cellular responses is a general mechanism for the activation of target cells by helper T lymphocytes and is not unique to antibody production.
Mutations in the CD40L gene result in a disease called the X-linked hyper-IgM syndrome, which is characterized by defects in antibody production, isotype switching, affinity maturation, and memory B cell generation in response to protein antigens, as well as deficient cellmediated immunity (see Chapter 20). Similar abnormalities are seen in CD40 or CD40L gene knockout mice. Interestingly, a DNA virus called the Epstein-Barr virus (EBV) infects human B cells and induces their proliferation. This may lead to immortalization of the cells and the development of lymphomas. The cytoplasmic tail of a transforming protein of EBV called LMP1 (latent membrane protein 1) associates with the same TRAF molecules as does the cytoplasmic domain of CD40, and this apparently triggers B cell proliferation. Thus, EBV LMP1 is functionally homologous to a physiologic B cell signaling molecule, and EBV has apparently co-opted a normal pathway of B lymphocyte activation for its own purpose, which is to promote survival and proliferation of cells that the virus has infected.
In addition to CD40L on helper T cells activating B cells, helper T cells also secrete cytokines that contribute to B cell responses. The best defined roles of T cell-derived cytokines in humoral immune responses are in isotype switching, described later. Several cytokines have also been implicated in the early steps of B cell proliferation and differentiation, but it is not clear if any are actually essential for these responses.
The initial interaction of activated helper T cells with antigen-specific B cells at the edge of the follicle induces some proliferation and differentiation of B cells and leads
FIGURE 11-10 Mechanisms of helper T cell-mediated B cell activation. Activated helper T cells that migrate toward the B cell zone express CD40L and their T cell receptors recognize peptide-class II MHC complexes on B cells that have been triggered by antigen and have in turn migrated to the interface between T and B cell zones. CD40L on the activated T helper cell then binds to CD40 on antigen-activated B cells and initiates B cell proliferation and differentiation. Cytokines bind to cytokine receptors on the B cells and also stimulate B cell responses. Two types of differentiation events may occur—the formation of extrafollicular foci and the induction of a germinal center B cell reaction.
Extrafollicular B cell activation; isotype switching; limited somatic mutation; short-lived plasma cells
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