FIGURE 11-13 Molecular events in T follicular helper cell generation and function. Activated B cells express ICOSL and signal to T helper cells. Triggering of ICOS and homotypic activation of SLAM family proteins on T cells result in differentiation into T follicular helper (Tfh) cells. SLAM-associated protein (SAP) is a signaling molecule required for Tfh cell differentiation. Tfh cells express the Bcl-6 transcription factor, secrete IL-21 and other cytokines, and activate B cells in the germinal center reaction.
the differentiation of T cells into TFH cells. The interactions between B cells and helper T cells are mediated by integ-rins and by members of the SLAM family of costimulators. A signaling molecule that associates with these SLAM family proteins in TFH cells is called SAP, and SAP signaling activates transcriptional regulators, particularly Bcl-6, that are required for TFH cell development. SAP is mutated in patients with a disease known as the X-linked lympho-proliferative syndrome, which is associated with defects in antibody and cytotoxic T cell responses (see Chapter 20). IL-21 secreted by TFH cells may facilitate germinal center B cell selection events and differentiation of activated B cells into plasmablasts. These helper T cells can secrete other cytokines that may be characteristic of TH1, TH2, and TH17 cells, and these cytokines can contribute to isotype switching. Germinal center formation is also dependent on CD40L:CD40 interactions. These may be critical for B cell proliferation, which is required for expansion of B cells in germinal centers, and also for isotype switching and affinity maturation. Therefore, germinal centers are defective in humans and in mice with genetic defects in T cell development or activation or with mutations of either CD40 or its ligand (see Chapter 20).
The architecture of lymphoid follicles and the germinal center reaction within follicles depend on the presence of follicular dendritic cells (FDCs). FDCs are found only in lymphoid follicles and express complement receptors (CR1, CR2, and CR3) and Fc receptors. These molecules are involved in displaying antigens for the selection of germinal center B cells, as described later. FDCs do not express class II MHC molecules and are not derived from progenitors in the bone marrow. In spite of their name, they are distinct from the class II MHC-expressing dendritic cells that capture antigens in tissues and transport them to lymphoid organs where they present peptides to T lymphocytes. The long cytoplasmic processes of FDCs form a meshwork around which germinal centers are formed. Proliferating B cells accumulate in the histologi-cally identifiable dark zone of the germinal center, which has few FDCs. The small nondividing progeny of the B cells migrate to the adjacent light zone, where they come into close contact with the processes of the abundant FDCs and also form intimate contacts with TFH cells, and this is where subsequent selection events occur (see Fig. 11-12). The rim of naive B cells in the follicle, surrounding the germinal center, is called the mantle zone.
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