Signal integration and crosstalk during thymocyte migration and emigration

• Published in: Nature reviews. Immunology Vol. 11; no. 7; pp. 469 - 477
• Main Authors: Love, Paul E., Bhandoola, Avinash
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2011; Nature Publishing Group
• Subjects: 631/250/1620/1840; 631/250/516; 631/80/84; 98; Animals; Antigens; Biomedical and Life Sciences; Biomedicine; Bone marrow; Cell migration; Cell Movement - immunology; Chemokines; Cytokines; Emigration; Humans; Immunology; Kinases; Ligands; Models, Immunological; Physiological aspects; Physiology; Receptors, Antigen, T-Cell - immunology; Receptors, Antigen, T-Cell - metabolism; Receptors, Chemokine - immunology; Receptors, Chemokine - metabolism; review-article; Signal Transduction - immunology; Stem cells; Stem Cells - immunology; Stem Cells - metabolism; T cell receptors; T cells; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Thymus gland; Thymus Gland - cytology; Thymus Gland - immunology; Thymus Gland - metabolism; United States; United States > US
• ISSN: 1474-1733; 1474-1741; 1474-1741
• DOI: 10.1038/nri2989

Key Points T cell development requires the migration of haematopoietic progenitors from the bone marrow to the thymus. T cell lineage potential is broadly distributed among primitive bone marrow-derived progenitor populations. However, the ability to migrate to the thymus is tightly regulated. Thymic homing has a molecular basis that is beginning to be understood. Known molecules implicated in thymic homing include P-selectin glycoprotein ligand 1 and the chemokine receptors CCR7 and CCR9. Migration of developing thymocytes through different regions of the thymus is crucial for normal T cell development and is regulated by multiple chemokine receptors, including CXCR4, CCR7 and CCR9. Crosstalk between these receptors and developmental receptors (the T cell receptor (TCR) and pre-TCR) regulates both thymocyte migration and thymocyte development. Thymocyte emigration is precisely timed to occur only after maturation is completed and after thymocytes are screened by negative selection to remove overtly autoreactive cells. The chemotactic receptor sphingosine-1-phosphate receptor 1 (S1P 1 ; encoded by S1PR1 ) has a crucial role in regulating thymocyte export. Current data suggest a model for thymocyte emigration in which TCR signalling controls the timing of export by regulating the expression of S1P 1 and CCR7, as well as that of CD69, which functions to downregulate S1P 1 surface expression. TCR signals inhibit S1pr1 transcription and upregulate CD69, thereby preventing thymocyte export. Cessation of TCR signalling induces S1pr1 transcription and downregulates CD69, rendering thymocytes susceptible to S1P 1 -mediated signalling and promoting thymocyte emigration. T cell progenitors must receive cues to instruct their homing to and entry into the thymus and, once there, positive and negative selection signals need to be synchronized with signals that control the migration of thymocytes within and out of the thymus. This Review focuses on recent advances in our understanding of thymocyte migration and highlights some outstanding questions. The thymus produces self-tolerant functionally competent T cells. This process involves the import of multipotent haematopoietic progenitors that are then signalled to adopt the T cell fate. Expression of T cell-specific genes, including those encoding the T cell receptor (TCR), is followed by positive and negative selection and the eventual export of mature T cells. Significant progress has been made in elucidating the signals that direct progenitor cell trafficking to, within and out of the thymus. These advances are the subject of this Review, with a particular focus on the role of reciprocal cooperative and regulatory interactions between TCR- and chemokine receptor-mediated signalling.