Upon activation by antigen, helper T cells express CD40 ligand (CD40L), which engages its receptor, CD40, on antigen-stimulated B cells and induces and many of the events in extracellular foci and germinal centers, including B-cell proliferation and differentiation into antibody-secreting cells (Fig. 1). This interaction is the principal mechanism by which helper T cells activate B cells. In addition to stimulating B-cell proliferation and differentiation, CD40 plays a critical role in Ig class switching and Ig V gene somatic mutations, discussed later.
Fig1. Mechanisms of helper T cell–mediated B-cell activation. Helper T cells that are activated by recognizing antigens presented by B cells express CD40 ligand (CD40L), which binds to CD40 on B cells and stimulates B-cell proliferation and differentiation. Cytokines produced by the helper T cells also contribute to B-cell responses.
CD40 is a member of the TNF receptor superfamily (see Chapter 10). Its ligand, CD40L (CD154), is a trimeric mem brane protein that is homologous to TNF. CD40 is constitutively expressed on B cells and CD40L is expressed on the surface of helper T cells that have been recently activated by antigen and costimulators. When these activated helper T cells interact physically with antigen-presenting B cells, CD40L binds CD40 on the B-cell surface. This results in conformational alteration of preformed CD40 trimers, which induces the association of cytosolic proteins called TRAFs (TNF receptor-associated factors) with the cytoplasmic domain of CD40. The TRAFs recruited to CD40 initiate enzyme cascades that lead to the activation and nuclear translocation of transcription factors, including NF-κB and AP-1, which collectively stimulate B-cell proliferation and increased synthesis and secretion of Ig. Similar signaling pathways are activated by TNF receptors in many cell types. As discussed later in the chapter, CD40 signaling induces the synthesis of an enzyme, activation-induced cytidine deaminase (AID), that is required for both class switching and mutation of Ig V genes.
CD40L and CD40 are also important for cell-mediated immunity, since helper T cells can activate antigen-presenting DCs and macrophages via interaction of CD40L on the T cells with CD40 on the DCs and macrophages.
Mutations in the CD40L gene cause a disease called the X-linked hyper-IgM syndrome, which is characterized by defects in antibody production, notably in class switching and affinity maturation, as well as deficient cell-mediated immunity. Similar abnormalities are also seen in patients with mutations in CD40 and in the gene encoding AID, the latter causing only humoral immune defects because AID is expressed in B cells but not in DCs or macrophages. 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 the EBV protein LMP1 (latent membrane protein 1) binds the same TRAF molecules as does the cytoplasmic domain of CD40, and this triggers B-cell proliferation. Thus, EBV LMP1 is functionally homologous to a physiologic B-cell signaling molecule, and EBV has 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 can infect.
