Upon TCR-mediated positive selection, developing thymocytes relocate within the thymus from the cortex to the medulla for further differentiation and selection. However, it is unknown how this cortex–medulla migration of thymocytes is controlled and how it controls T cell development. Here we show that in mice deficient for CCR7 or its ligands mature single-positive thymocytes are arrested in the cortex and do not accumulate in the medulla. These mutant mice are defective in forming the medullary region of the thymus. Thymic export of T cells in these mice is compromised during the neonatal period but not in adulthood. Thymocytes in these mice show no defects in maturation, survival, and negative selection to ubiquitous antigens. TCR engagement of immature cortical thymocytes elevates the cell surface expression of CCR7. These results indicate that CCR7 signals are essential for the migration of positively selected thymocytes from the cortex to the medulla. CCR7-dependent cortex–medulla migration of thymocytes plays a crucial role in medulla formation and neonatal T cell export but is not essential for maturation, survival, negative selection, and adult export of thymocytes.

The systemic administration of keratinocyte growth factor (KGF) enhances T-cell lymphopoiesis in normal mice and mice that received a bone marrow transplant. KGF exerts protection to thymic stromal cells from cytoablative conditioning and graft-versus-host disease-induced injury. However, little is known regarding KGF's molecular and cellular mechanisms of action on thymic stromal cells. IntroductionDecreased T-cell cellularity and a skewed TCR repertoire are hallmarks of an immune deficiency commonly observed in old age, as a consequence of general infectious diseases and aggressive lymphocyte-depleting therapies for diverse malignancies. [1][2][3][4] The regeneration of a phenotypically and functionally normal T-cell compartment is curtailed for an extended period of time in patients receiving a hematopoietic stem cell transplant (HSCT). [5][6][7] This lack in T-cell reconstitution is associated with opportunistic infections, the reactivation of latent viral and parasitic infections, chronic inflammation, and autoimmunity. 3,4 Following cytoablative therapy, the recovery of the T-cell compartment relies on 2 independent pathways, that is, the expansion of peripheral T cells and, alternatively, the de novo production of T cells in the thymus. 1,2,7-10 The latter assures the generation of a population of naive T cells expressing a diverse repertoire of TCR specificities. 5,7,8,10,11 The extent of thymusdependent T-cell reconstitution correlates directly with thymic size following immune ablation and hematopoietic stem cell (HSC)-derived reconstitution 7,12 but is inversely related to age and transplant-related toxicities such as graft-versus-host disease (GVHD). 10,[13][14][15][16][17] The generation of new T cells of donor origin depends on the migration of hematopoietic precursors to the thymus. Normal thymic T-cell development is in turn contingent on the regular maintenance of the stromal microenvironment. However, age-related thymic involution 18 and injury from radiation, 19 GVHD, 20 chemotherapy, 12,21 or infection 3,4,12,[18][19][20][21][22][23] preclude normal thymopoiesis to occur as they directly affect thymic epithelial cells (TECs). There has been considerable interest in identifying strategies to prevent TEC injury. Recently, robust T-cell lymphopoiesis has been maintained in myeloablated HSCT recipients by pretransplantation administration of different factors such as 24,25 androgen antagonists, 26 and fibroblast growth factor 7 (Fgf7; aka, keratinocyte growth factor [KGF]). 20,27-29 KGF belongs to the family of the structurally related Fgfs and is a potent epithelial cell mitogen. 27,30 KGF is expressed under physiological conditions within the thymus both by mesenchymal cells and by T cells at specific developmental stages. To exert its biologic activity, KGF activates the IIIb variant of the FgfR2 receptor (FgfR2IIIb), which is expressed within the thymus exclusively on TECs. 31 Experiments using mice deficient for FgfR2IIIb or the removal of mesenchyme from normal embryos revealed the importa...

During embryonic development, T-lymphoid precursor cells colonize the thymus. Chemoattraction by the fetal thymus is thought to mediate T-precursor cell colonization. However, the molecules that attract Tprecursor cells to the thymus remain unclear. By devising time-lapse visualization in culture, the present results show that alymphoid fetal thymus lobes attract Tprecursor cells from fetal liver or fetal blood. CD4 ؊ CD8 ؊ CD25 ؊ CD44 ؉ fetal thymocytes retained the activity to specifically re-enter the thymus. The attraction was predominantly due to I-A-expressing thymic epithelial cells and was mediated by pertussis toxin-sensitive G-protein signals. Among the chemokines produced by the fetal thymus, CCL21, CCL25, and CXCL12 could attract CD4 ؊ CD8 ؊ CD25 ؊ -CD44 ؉ fetal thymocytes. However, fetal thymus colonization was markedly diminished by neutralizing antibodies specific for CCL21 and CCL25, but not affected by anti-CXCL12 antibody. Fetal thymus colonization was partially defective in CCL21-deficient plt/plt mice and was further diminished by anti-CCL25 antibody. These results indicate that CCL21 is involved in the recruitment of T-cell precursors to the fetal thymus and suggest that the combination of CCL21 and CCL25 plays a major role in fetal thymus colonization. (Blood. 2005;105:31-39)