The ontogeny and organization of the lymphoid system

The organization of the lymphoid system reflects 2 phases in the development and function of its component lymphocytes; a primary continuous genesis of 2 lineages of lymphocytes, B and T cells, is followed by a secondary wave of cell production and differentiation dependent on antigenic stimulation. Primary B cell genesis occurs multifocally before birth and in the bone marrow thereafter. Early progenitor cells give rise to proliferating pre-B cells containing free cytoplasmic mu chains, and thus to small lymphocytes expressing surface immunoglobulins, IgM, and IgD. Somatic rearrangement of genes in precursor cells produces clones of B cells, each member having an identical antigen-binding specificity. Primary T cell genesis occurs in the thymus, where an epithelial cell environment induces stem cells entering from embryonic mesoderm and postnatal bone marrow to proliferate extensively and to differentiate in discrete anatomical locations into 2 main sublineages, distinguishable by surface membrane markers. Primary B and T cells migrate rapidly to the spleen, lymph nodes, and mucosal lymphoid tissues where they may either die or be activated by antigens presented on macrophages and dendritic cells. Proliferation of activated B cells produces expanded clones of antigen-specific B memory cells in transient germinal centers. The secondary wave of B and T cells enters a pool of long-lived lymphocytes, which recirculate repeatedly between the blood and lymphoid organs, showing characteristic kinetics, migratory routes, and tissue localization. The entry of antigens accelerates local lymphocyte traffic and the retention of antigen-specific cells to promote an effective immune response. Despite important advances, many challenges remain in understanding the early differentiation, microenvironmental organization, and regulation of lymphoid cell populations in vivo.