T-cell development

Premature expression of chemokine receptor CCR9 impairs T cell development. Uehara, S. et al. J. Immunol. 176, 75–84 (2006)

Only late CD4−CD8− double-negative (DN) thymocytes and CD4+CD8+ double-positive thymocytes express CC-chemokine receptor 9 (CCR9). To investigate whether expression of CCR9 controls the migration of thymocytes and their retention in the thymus, Uehara et al. generated transgenic mice in which CCR9 was expressed throughout T-cell development. CD4+ and CD8+ single-positive (SP) thymocytes could exit the thymus, indicating that CCR9 downregulation is not essential for SP thymocyte emigration. By contrast, ectopic expression of CCR9 by early DN thymocytes partially blocked thymocyte development at the DN3 stage, and CD25+ thymocytes (DN2 and DN3 thymocytes) were found throughout the cortex rather than at the subcapsular region. These results indicate that the timing of CCR9 expression is important for normal thymocyte development and that this might be because CCR9 controls CD25+ thymocyte localization.

Haematopoiesis

Glycogen synthase kinase-3 is an in vivo regulator of hematopoietic stem cell repopulation. Trowbridge, J. J. et al. Nature Med. 12, 89–98 (2006)

Glycogen synthase kinase 3 (GSK3) regulates several signalling pathways (such as the Notch and WNT signalling pathways) that affect the in vitro function of haematopoietic stem cells (HSCs). In this study, non-obese diabetic–severe combined immunodeficient mice were transplanted with HSCs from normal mice in the presence or absence of an ATP-competitive inhibitor of GSK3. Treatment with the GSK3 inhibitor increased recipient haematopoietic-cell reconstitution in both the short and the long term and thereby increased recipient survival. Further analysis showed that the GSK3 inhibitor increased the production of progenitor cells while maintaining the number of HSCs, leading the authors to suggest that treatment with GSK3 inhibitors might be a useful therapeutic approach to increase recipient haematopoietic-cell reconstitution after HSC transplantation.

Haematopoiesis

Antagonistic effect of CCAAT enhancer-binding protein-α and Pax5 in myeloid or lymphoid lineage choice in common lymphoid progenitors. Hsu, C.-L. et al. Proc. Natl Acad. Sci. USA 103, 672–677 (2006)

Although lymphoid-lineage-committed progenitors, such as common lymphoid progenitors (CLPs) and pro-T cells, are mainly destined to become lymphocytes, they maintain a latent myeloid differentiation potential, which can be initiated by stimulation through ectopic interleukin-2 receptor (IL-2R). This study shows that IL-2R triggering of CLPs and pro-T cells results in rapid upregulation of the myeloid-related transcription factor CCAAT enhancer-binding protein-α (C/EBPα). Moreover, ectopic expression of C/EBPα in these cells leads to myeloid-cell development. C/EBPα expression completely suppressed expression of the B-cell-lineage transcription factor PAX5 in CLPs and pro-T cells. By contrast, IL-2R stimulation of pro-B cells did not lead to lineage conversion, owing to insufficient downregulation of PAX5 expression by C/EBPα, indicating that complete loss of PAX5 is crucial for lymphoid-to-myeloid-lineage conversion.