T cells do not reenter the thymus purely as a result of surgical perturbations or from the intravenous injection of a bolus of mature T cells. with the immigration of bone marrow-derived progenitor cells, and ends with the generation APD668 of self-tolerant, lineage committed T cells capable of performing an array of immune functions upon recognition of antigen in the context of molecules encoded by self major histocompatibility (MHC) genes (reviewed in1). The T cell precursors that first enter the thymus do not express the antigen recognition machinery, lacking both the coreceptors (CD4 and CD8) that focus T cell attention on MHC molecules and the T cell receptors for antigen recognition (TCR and TCR). The genes encoding these highly diverse TCRs undergo a carefully programmed series of DNA rearrangements triggered within the thymus in a stepwise fashion, beginning in CD4CD8(double negative or DN) thymocytes (reviewed in2). For conventional TCR T cells that recognize peptide antigens presented by classical MHC molecules, commitment to the T cell lineage is sealed by rearrangement of the TCR gene. The process of selection tests the accuracy of this rearrangement event, and drives the proliferation and CD4 and CD8 coreceptor expression by those cells expressing a Mouse monoclonal to SUZ12 functional TCR chain (defined as one that pairs with the product of the unrearranged pre-T gene)3. The result is a large population of CD4+CD8+(double positive or DP) thymocytes that initiate TCR rearrangement. Accurate TCR rearrangement along with successful TCR chain pairing and surface expression are required for positive selection, the second critical checkpoint for maturing T cells. Positive selection is driven by the successful, low affinity interaction between the expressed TCR receptor on a DP thymocyte and self-peptide in the context of self-MHC3,4. Positive selection rescues DP thymocytes from the alternative destiny of programmed cell death by neglect, and drives the accurate alignment between coreceptor expression and lineage commitment1,3,4. This process results in a population of CD4+CD8(single positive or SP) thymocytes that can differentiate into helper T cells upon further recognition of peptide presented by MHC class II molecules, and CD4CD8+SP thymocytes that can differentiate into killer T cells upon encounter with antigen presenting cells whose MHC class I molecules carry the appropriate peptides. At the DP or SP stages, thymocytes are subjected to negative selection, the third checkpoint that regulates T cell development. During this process, central to the establishment of self-tolerance among developing T cells, TCR+thymocytes that react with inappropriately high avidity to self peptide/MHC complexes are deleted57. The 1% of thymocytes that successfully transit selection, positive selection, and negative selection undergo additional maturation that promotes their regulated exit from the thymus. After further maturation in the lymphoid periphery, these recent thymic emigrants join the pool of APD668 mature peripheral T cells. The induction of self-tolerance among any remaining self-reactive T cells continues in the lymphoid periphery by several means, including through the activity of regulatory T cells APD668 (Tregs, reviewed in8). The population of mature peripheral T cells recirculates from blood to the lymph and back again, patrolling the spleen and lymph nodes for foreign invaders. Lymphocyte recirculation is a carefully controlled, multistep process, regulated by the expression on lymphocytes of homing receptors (including integrins and chemokine receptors) and by the expression or elaboration by stromal elements of addressins, the ligands for lymphocyte homing receptors (reviewed in911). As with most developmental systems, the close association.