T-cell differentiation (top): Antigen-independent: The earliest antigen-independent stages of T cell differentiation occur in the bone marrow; later stages occur in the thymic cortex. The exact site at which precursor cells become committed to the T lineage is not known, since the thymus contains cells that can differentiate into either T cells or natural killer (NK) cells, but not B cells. In addition to providing a pool of mature T cells through proliferation of precursor cells, the thymus plays a major role in the selection of T cells, so that the resulting pool of mature T cells recognize "self" HLA molecules, in which antigen is presented to T cells, and do not react to "self" antigens. Mature, naive (virgin) T cells have the morphologic appearance of small lymphocytes. These cells leave the thymus and can be found in the in the thymic medulla, the peripheral circulation, and in the paracortex of lymph nodes. Antigen-dependent: On encountering antigen, mature T cells transform into immunoblasts, which are large cells with prominent nucleoli and basophilic cytoplasm that may be indistinguishable from B immunoblasts. Antigen-dependent T cell reactions occur in the paracortex of lymph nodes and the periarteriolar lymphoid sheath of the spleen, as well as at extranodal sites of immunologic reactions. Fully differentiated T effector cells are small lymphocytes, morphologically similar to other non-proliferating lymphocytes of either T or B type. Activated cytotoxic T cells of either CD4 or CD8 type typically have intracytoplasmic azurophilic granules (large granular lymphocytes). The majority of T cells in the circulation and in most lymphoid tissues are αβ+; γδ T cells are more numerous in mucosae and in the spleen. B-cell differentiation (bottom): Antigen-independent: Fetal early B-cell development occurs in the liver, bone marrow, and spleen, while in adults it is restricted to the bone marrow. Cells with the morphologic and immunologic features of precursor B cells can be found in normal and regenerating bone marrow, where they correspond to the lymphocyte-like cells known as hematogones. Naive B cells are small resting lymphocytes. They circulate in the blood and also comprise a majority of the B cells in primary lymphoid follicles and follicle mantle zones (so-called recirculating B cells). Antigen-dependent: When naive B cells encounter antigen they transform into proliferating blast cells in the T zone of lymph nodes. Some of the daughter cells mature into IgM-secreting, short-lived plasma cells, producing the IgM antibody of the primary immune response. Later in the primary response, the proliferating IgM positive B-blasts migrate into the center of the primary follicle and fill the follicular dendritic cell (FDC) meshwork, forming a germinal center and pushing aside the naive B cells of the primary follicle, which form a mantle zone. The B-blasts differentiate into centroblasts (large noncleaved follicular center cells), which accumulate at one pole of the germinal center, forming the "dark zone." Centroblasts are large proliferating cells with vesicular nuclei, one to three prominent, peripheral nucleoli, and a narrow rim of basophilic cytoplasm. Centroblasts undergo somatic mutation of the immunoglobulin (Ig) variable region genes (IgV), which alters the affinity for antigen of the antibody that will be produced by the cell. This somatic mutation thus results in marked intraclonal diversity of antibody combining sites in a population of cells derived from only a few precursors. Centroblasts are mature to nonproliferating medium-sized cells with irregular nuclei, inconspicuous nucleoli, and scant cytoplasm, called centrocytes (small or large cleaved follicular center cells). These accumulate in the opposite pole of the germinal center, known as the "light zone", which contains a high concentration of FDCs. Centrocytes whose Ig gene mutations have resulted in decreased affinity for antigen rapidly die by apoptosis (programmed cell death); the prominent "starry sky" pattern of phagocytic macrophages seen in germinal centers at this stage is a result of the apoptosis of centrocytes. In contrast, centrocytes whose Ig gene mutations have resulted in increased affinity are able to bind to antigen trapped on the processes of FDCs, which "rescues" them from apoptosis. Driven by signals from FDC and the T cells present in the light zone, the rescued centrocytes may either become memory B cells, or they may switch their Ig heavy chain to IgG or IgA and become immunoglobulin-secreting plasma cells. Antigen-specific memory B cells generated in the germinal center reaction leave the follicle and reappear in the outer mantle zone, to form a "marginal zone". Marginal zone B cells have slightly irregular nuclei, resembling those of centrocytes, but with more abundant, pale cytoplasm. Memory B cells are also detectable in the peripheral blood. Immunoglobulin class-switched plasma cells accumulate in the lymph node medulla, but it appears that the immediate precursor of the bone marrow plasma cell leaves the node and migrates to the bone marrow.