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B cell

FIGURE 11-12 The germinal center reaction in a lymph node. B cells that have been activated by T helper cells at the edge of a primary follicle migrate into the follicle and proliferate, forming the dark zone of the germinal center. Germinal center B cells undergo extensive isotype switching. Somatic hypermutation of Ig V genes occur in these B cells, and they migrate into the light zone, where they encounter follicular dendritic cells displaying antigen and Tfh cells. B cells with the highest affinity Ig receptors are selected to survive, and they differentiate into antibody-secreting or memory B cells. The antibody-secreting cells leave and reside in the bone marrow as long-lived plasma cells, and the memory B cells enter the recirculating pool.

Helper T cell within 5 days, a single lymphocyte may give rise to almost 5000 progeny. The progeny of the proliferating B cells in the germinal center are smaller cells, sometimes called centrocytes, that undergo differentiation and selection processes in the "light zone," described later. B cells in germinal centers express a transcriptional repressor known as Bcl-6 (for B cell lymphoma gene 6), whose role is described later when we consider the transcriptional regulation of B cell fate.

In addition to the chemokine receptor CXCR5, TFH cells are characterized by the expression of ICOS (inducible costimulator), the cytokine IL-21, and the transcription factor Bcl-6. TFH cells have a phenotype that makes them distinct from the TH1, TH2, TH17, and Treg subsets described in Chapters 9 and 10. It is possible that TFH cells can develop from naive CD4+ T cells or from polarized T cell subsets that retain developmental plasticity. The "signature" cytokine secreted by TFH cells is IL-21. It is required for germinal center development and also contributes to the generation of plasma cells in the germinal center reaction. In addition to IL-21, TFH cells secrete other cytokines, including IFN-y and IL-4 (but at lower levels than differentiated TH1 and TH2 cells, respectively), and all these play important roles in isotype switching.

The mechanisms that drive the development of TFH cells from CD4+ cells and the mechanisms by which TFH cells activate B cells are not fully understood. A number of molecules on B cells and helper T cells are known to play key roles in these processes (Fig. 11-13). The costimulator ICOS, which is related to CD28 and is expressed on Tfh cells, is essential for the germinal center reaction. The interaction of ICOS with ICOS ligand on B cells promotes

Induction of

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