Figure 1: The intra- and extrathymic origin of T regulatory (Treg) lymphocytes. The bone marrow-derived pre-T lymphocytes arrive at the thymus microenvironment as double negative CD4CD8 cells, which are engulfed by thymic nurse cells, where they mature to CD4+ or CD8+ lymphocytes or are negatively selected. A reduced proportion (0.05%) of the CD4+ lymphocytes become regulatory cells by expressing CD25, Foxp3, CTLA-4, and other molecules. When this subpopulation of natural T regulatory (nTreg) lymphocytes is mature, they are released from the medullary thymic nurse cells, leave the thymus, and go into the blood and peripheral lymphoid organs where they release IL-10 and TGF-β suppressor cytokines that downmodulate the functions of other cells from the immune system. A different subpopulation of T regulatory cells can be experimentally induced from CD8+ cytotoxic lymphocytes located outside the thymus. These lymphocytes exert an in vitro suppressor activity through IL-10, IL-4, and TGF-β; they are called inducible T regulatory (iTreg) lymphocytes and have been found as infiltrating cells with an effective antitumor activity.