enter the T cell pathway as they immigrate to the thymus. The most primitive cells in the thymus are the early thymocyte progenitors (ETP), which retain all lymphoid and myeloid potential but exist only transiently, rapidly differentiating into T and NK lineages. (Medical Immunology, p. 118) Stage Two: Proliferative Expansion and T Lineage Commitment Final commitment to the T cell lineage occurs within the thymic microenvironment, the microscopic structures of the thymus where T cells are nurtured. The most primitive T cells retain pluripotential ability and can differentiate into cells of the myeloid or lymphoid lineages (B cells, DC, T cells, or NK cells). More differentiated double negative T cells (DN2 cells) have more limited potentiality but are not yet fully restricted to the T cell lineage (they can still develop into DC, T cells, or NK cells). Later on, they are fully committed to the T cell lineage- when thymocytes expressing Notch1 receptors engage thymic stromal cells expressing Notch1 ligands, the thymocytes become finally committed to the T-cell lineage. See Gallery Image "Double Negatives" With the commitment to the T cell lineage, begins a very complex process known as TCR gene rearrangement. This creates an enormous diversity of T cells bearing antigen receptors. Afterward some T cells leave the thymus to migrate to the skin and mucosae. Stage Three: β-Selection Stage Four: T Cell Receptors Selection Only 2% to 3% of the differentiating thymocytes, those that express TcR capable of interaction with MHC molecules, but tolerant to self-peptides, survive the Stage Four selection process. Stage Five: Continuing Differentiation in the Periphery It was previously believed that the human thymus remained active as the site of T cell differentiation only until early adulthood and that later in adult life the thymus atrophies, perhaps even vanishing. Recent reports indicate that the human thymus is active throughout adult life. Thus several factors may contribute to the supply of T cells in adult life: generation in the thymus, extra-thymic differentiation, and the fact that memory T cells are long-lived and survive for decades. T cell types Unconventional T cells The thymus also gives rise to the so-called ‘unconventional T cells’ such at γδ T cells, natural killer T cells (NKT) and regulatory T cells (Treg). γδ T cells γδT cells represent only 1% to 5% of the circulating T cells, but are abundant in the mucosal immune system and the skin, where they