The initial T-B interaction, which occurs outside the lymphoid follicles, results in the production of low levels of antibodies, which may be of switched iso types (described next) but are generally of low affinity (see Fig. 1-B). The plasma cells that are generated in these extra-follicular foci are typically short-lived and produce antibodies for a few weeks, and few memory B cells are generated.

Fig1. Sequence of events in helper T cell–dependent antibody responses. A, T and B lymphocytes independently recognize the antigen in different regions of peripheral lymphoid organs and are activated. The activated cells migrate toward one another and interact at the edges of lymphoid follicles. B, Antibody- secreting plasma cells are initially produced in the extrafollicular focus where the antigen-activated T and B cells interact. Some of the activated B and T cells migrate back into the follicle to form the germinal center, where the antibody response develops fully.

Many of the events in fully developed antibody responses occur in germinal centers that are formed in lymphoid follicles and require the participation of a specialized type of helper T cell (Fig. 2). Some of the activated helper T cells express high levels of the chemokine receptor CXCR5, which draws these cells into the adjacent follicles. The CD4+ T cells that migrate into B cell–rich follicles are called follicular helper T (Tfh) cells. The generation and function of Tfh cells are dependent on a receptor of the CD28 family called inducible costimulator (ICOS), which binds to its ligand expressed on B cells and other cells. Inherited mutations in the ICOS gene are the cause of some antibody deficiencies . Tfh cells may secrete cytokines, such as interferon (IFN)-γ, interleukin (IL)-4, or IL-17, which are characteristic of Th1, Th2, and Th17 subsets; the role of these cytokines in B cell responses is described below. In addition, most Tfh cells secrete the cytokine IL-21, which has an important but incompletely understood role in Tfh cell function.

Fig2. The germinal center reaction. 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 and somatic mutation of Ig genes and migrate into the light zone, where B cells with the highest-affinity Ig receptors are selected to survive, and they differentiate into plasma cells or memory cells, which leave the germinal center. The right panel shows the histology of a secondary follicle with a germinal center in a lymph node. The germinal center includes a basal dark zone and an adjacent light zone. The mantle zone is the part of the follicle outside the germinal center.

A few of the activated B cells from the extrafollicular focus migrate back into the lymphoid follicle, together with Tfh cells, and begin to divide rapidly in response to signals from the Tfh cells. It is estimated that these B cells have a doubling time of approximately 6 hours, so one cell may produce several thousand progeny within a week.

The region of the follicle containing these proliferating B cells is the germinal center, so named because it was once incorrectly thought that these were the sites where new lymphocytes are generated (germinated). In the germinal center, B cells undergo extensive isotype switch ing and somatic mutation of Ig genes; both processes are described below. The highest-affinity B cells are the ones that are selected during the germinal center reaction to differentiate into memory B cells and long-lived plasma cells. Proliferating B cells reside in the dark zone of the germinal center (see Fig. 2), while selection occurs in the less dense light zone.